Wax foamable vehicle and pharmaceutical compositions thereof

ABSTRACT

Unique foamable vehicles or carriers comprising at least one wax, waxy substance, counterpart or derivative, a stabilizer, water, and a propellant are provided. In some embodiments, the wax is a liquid wax. In some embodiments, the wax includes a solid wax and a liquid wax. The compositions are substantially free of crystals. The components are selected to provide a composition that is substantially resistant to aging and to phase separation, and/or can substantially solubilize and or stabilize active ingredients. Pharmaceutical and cosmetic compositions with potentially enhanced skin delivery and their uses are also provided.

This application claims the benefit of priority under 35 U.S.C. § 119(e)to co-pending U.S. Provisional Application No. 60/954,525 filed Aug. 7,2007, entitled “Wax Foamable Vehicle And Pharmaceutical CompositionsThereof”, which is incorporated in its entirety by reference.

BACKGROUND

This invention relates to foamable pharmaceutical and cosmeticcompositions.

External topical administration is an important route for theadministration of drugs in disease treatment. Many groups of drugs,including, for example, antibiotic, anti-fungal, anti-inflammatory,anesthetic, analgesic, anti-allergic, corticosteroid, retinoid andanti-proliferative medications are preferably administered inhydrophobic media, namely ointment. However, ointments often form animpermeable barrier, so that metabolic products and excreta from thewounds to which they are applied are not easily removed or drained away.Furthermore, it is difficult for the active drug dissolved in thecarrier to pass through the white petrolatum barrier layer into thewound tissue, so the efficacy of the drug is reduced. In addition,ointments and creams often do not create an environment for promotingrespiration of the wound tissue and it is not favorable to the normalrespiration of the skin. An additional disadvantage of petroleumjelly-based ointments and creams relates to the greasy feeling leftfollowing their topical application onto the skin, mucosal membranes andwounds.

Foams are considered a more convenient vehicle for topical delivery ofactive agents. There are several types of topical foams, includingaqueous foams, such as commonly available shaving foams; hydroalcoholicfoams, emulsion-based foams, comprising oil and water components, andoleaginous foams, which consist of high oil content. In skin therapy,oil containing foams are preferred, since oil contributes to skinprotection and moisturization, which improve the therapeutic effect ofthe formulation.

Fatty acids and fatty alcohols counterparts and derivatives have beenused in foamable formulations as foam adjuvants usually in low amountsof up to about 5% and may possibly have a therapeutic effect in thetreatment of a variety of skin disorders and/or conditions. Some arewaxy solids while others are liquid at room temperature and pressure.For example, in the case where the carbon backbone chain is 18C, stearicacid and stearyl alcohol are waxy solids whilst isostearic acid, oleicacid and oleyl alcohol are liquids. The significance of this differencein liquidity of molecules having the same or similar backbone chain onfoamable compositions is investigated herein.

Jojoba oil has been used in foamable formulations usually in relativelylow amounts of up to about 10% and may possibly have a therapeuticeffect in the treatment of a variety of skin disorders and/orconditions.

Branched (i.e., non-straight chain) waxes like oleic acid are known tocontribute to the skin penetration of an active agent.

Aldara, a commercially available topical cream containing imiquimod asactive agent, uses 25% isostearic acid as a solubilizing agent.

Formulations comprising micronized imiquimod with fatty acids and fattyalcohols are known. The level of fatty acid in such formulations,however, is minimized to avoid idiosyncrasy. As such, these formulationsare essentially free of isostearic acid. Moreover, such formulations arecream formulations and foam compositions of such formulations have notbeen specifically disclosed.

Emulsion based foam formulations comprising imiquimod and fatty acids insufficient amount to solubilize imiquimod have been disclosed. Theseformulations are limited in the amount of isostearic acid that can bepresent in the formulation (typically 25% or less).

Aqueous foam compositions comprising partially neutralized fatty acidsas organic solvents have been generally disclosed in the art. However,specific compositions containing additional components, such aspolymers, surfactants, and liquid fatty acids have not been disclosed.The stability of such foams relies upon the presence of a component suchas triethanolamine, as well as basic active components (such asimiquimod) to neutralize fatty acid and water foams.

Foam using very high amounts of anionic surfactants 20% to 95% withC10:0 (e.g., 1-decanol) fatty alcohol has been described in the art. Thelarge amounts of surfactant result in a mesomorphic phase whichsolubilizes the propellant. The use of high levels of anionicsurfactants and C10:0 fatty alcohol, which are irritants, renders thesecompositions unsuitable for use on the skin and eyes, and, in somecases, harmful, particularly in the eyes.

There remains an unmet need for improved, easy to use, vehicles and foamformulations, comprising wax, waxy substances, counterparts andderivatives thereof in preferably in substantial or higherconcentrations which can effectively deliver and/or deposit variousactive agents into and onto the skin and/or other target sites and arerelatively non-irritating and thus suitable for use by people havingsensitive skin, body cavities and mucosal surfaces. Significantly thereremains an unmet need for such vehicles and foam formulations that aresubstantially free from crystals. Accordingly, in some embodiments, theformulations described herein are free from crystals. In someembodiments, the formulations are free from an insoluble phase or, insome embodiments, free from insoluble matter. The presence of crystalsindicates that one or more ingredients are not solubilized. Inconsequence amongst other things the formulation may be unstable, may bevariable, may deliver unreliable amounts of active ingredients and maycause irritation and thus be unsuitable for therapeutic use.Additionally substantial crystal formation in a foamable formulation mayinterfere with foam release. In some embodiments, the formulations arefree from crystals yet still include a suspension of solid matter orparticles. In some embodiments, the solid matter or particles are notcrystalline. Examples of such solid matter include, without limitation,microsponges, ground seed, metallic particles and active agents inparticle form (e.g., benzyl peroxide).

There is a need for such vehicles and foam formulations in which thereis a relatively low level of surfactants. Surfactants can be irritantsparticularly at higher levels. Repeated use of formulations with higherlevels of surfactants on the skin can result in depletion of hydrophobicsubstances and dry skin.

High levels of surfactant can result in the formation of a mesomorphicphase. The mesomorphic phase can absorb propellant and may increaseirritation, depletion of fats and dry skin. There is a need for suchvehicles and foam formulations in which there is no mesomorphic phase

SUMMARY

The present invention relates to aqueous wax emulsion compositions.

In one aspect, foamable compositions are provided which include (a) awax, (b) a stabilizer component, (c) water, and (d) a propellant. Insome embodiments, the wax is a liquid wax. In other embodiments, the waxis a combination of a solid wax and a liquid wax. In some embodiments,the wax, for example the liquid wax or the solid wax, includes at leastone fatty acid or at least one fatty alcohol. In some embodiments, whenthe liquid wax includes at least one fatty acid, the fatty acid ispresent in the composition at a concentration of at least about 35% byweight. In some embodiments, when the liquid wax includes at least onefatty alcohol, the fatty alcohol is present in the composition at aconcentration of at least about 12% by weight. In some embodiments, whenthe composition includes a solid wax, the solid wax is present in thecomposition at a concentration of at least about 7% by weight. In one ormore embodiments all the ingredients are dissolved. In furtherembodiments the composition is substantially free from crystals, e.g.,free of an insoluble phase. Assessing whether a composition is free fromcrystals or free of an insoluble phase is performed by techniques knownto those of skill in the art. One exemplary technique for assessing thepresence of crystals or an insoluble phase in the compositions describedherein is by visual inspection, e.g., using light microscopy, asdescribed in further detail herein. In some embodiments the compositionincludes at least one active agent. In certain embodiments the activeagent is soluble in the composition.

In one aspect, foamable compositions are provided which include (a)jojoba oil, (b) a stabilizer component, (c) water, and (d) a propellant.In some embodiments, the jojoba oil is present in the composition at aconcentration of at least about 10% by weight.

In some embodiments, the stabilizer component includes a non-ionicsurface active agent, a polymeric agent or a mixture of a non-ionicsurface active agent and a polymeric agent. Exemplary polymeric agentsinclude, without limitation a bioadhesive agent, a gelling agent, a filmforming agent and a phase change agent. In some embodiments, thepolymeric agent is present in the composition at a concentration ofabout 0.01% to about 5% by weight.

In some embodiments, the propellant is a liquefied hydrocarbon gaspropellant. In some embodiments, the ratio of the combination of thewax, the stabilizer component and the water to the propellant is about100:3 by weight to about 100:35 by weight.

In some embodiments, the composition is substantially free from crystalsand is substantially flowable.

In some embodiments, the foamable composition is stored in a pressurizedcontainer. Upon release from the pressurized container, the resultingfoam is breakable.

In one aspect, a foamable composition is provided that includes:

a. a liquid wax including at least one fatty acid or at least one fattyalcohol;

b. a stabilizer component including a non ionic surface-active agent, apolymeric agent or a mixture thereof;

c. water; and

d. a liquefied hydrocarbon gas propellant, wherein the ratio of theliquid wax, the stabilizer and water to the gas propellant is about100:3 by weight to about 100:35 by weight.

When the liquid wax includes at least one fatty acid, the fatty acid ispresent in the composition at a concentration of at least about 35% byweight. When the liquid wax includes at least one fatty alcohol, thefatty alcohol is present in the composition at a concentration of atleast about 12% by weight. The composition is substantially free fromcrystals and is substantially flowable. When the stabilizer componentincludes a polymeric agent, the polymeric agent is present in thevehicle composition at a concentration of about 0.01% to about 5% byweight. The polymeric agent is a bioadhesive agent, a gelling agent, afilm forming agent or a phase change agent. Upon release from apressurized container, the foam produced is breakable.

In an embodiment the composition further includes a solid wax.

In another aspect, a foamable composition is provided that includes

a. at least about 7% by weight of a solid wax;

b. a liquid wax wherein the liquid wax includes at least one fatty acidor at least one fatty alcohol

c. a stabilizer including a non ionic surface-active agent, a polymericagent or a mixture thereof;

d. water; and

e. a liquefied hydrocarbon gas propellant, wherein the ratio of thesolid wax, the liquid wax, the stabilizer and water to the gaspropellant is about 100:3 by weight to about 100:35 by weight.

The composition is substantially free from crystals and is substantiallyflowable. When the stabilizer component includes a polymeric agent, thepolymeric agent is present in the vehicle composition at a concentrationof about 0.01% to about 5% by weight. The polymeric agent is abioadhesive agent, a gelling agent, a film forming agent or a phasechange agent. Upon release from a pressurized container, the foamproduced is breakable.

In some embodiments, the composition includes at least one liquid fattyacid. The liquid fatty acid is present in the composition at aconcentration of at least about 35% by weight. In some embodiments, thecomposition includes at least one liquid fatty alcohol. The liquid fattyalcohol is present in the composition at a concentration at least about12% by weight.

In one or more embodiments the wax foamable compositions further includean active agent.

In a further aspect, a foamable composition is provided that includes:

a. at least about 10% by weight jojoba oil;

b. a stabilizer component including a surface-active agent, a polymericagent or a mixture thereof;

c. water; and

d. a liquefied hydrocarbon gas propellant, wherein the ratio of thecomponent, the stabilizer and water to the gas propellant is about 100:3by weight to about 100:35 by weight.

The composition is substantially free from crystals and is substantiallyflowable. When the stabilizer component includes a polymeric agent, thepolymeric agent is present in the vehicle composition at a concentrationof about 0.01% to about 5% by weight. The polymeric agent is abioadhesive agent, a gelling agent, a film forming agent or a phasechange agent. Upon release from a pressurized container, the foamproduced is breakable.

In one or more embodiments the jojoba foamable composition furtherincludes an active agent.

In some embodiments, there are provided vehicles and foam formulationsin which the hydrophobic wax is liquid wax. In particular, in someembodiments, there are provided formulations where the wax includes aliquid fatty acid. Similarly there are provided in some embodimentsformulations where the wax includes a liquid fatty alcohol. In otherembodiments, there are further provided formulations where the liquidwax includes at least one fatty acid and at least one fatty alcohol. Thefatty wax is present in the composition at a concentration of at leastabout 30 wt %; at least about 35 wt %; at least about 40 wt %; at leastabout 50 wt %; or at least about 60 wt %. The fatty alcohol is presentin the composition at a concentration of at least about 7.5 wt %; atleast about 10 wt %; at least about 20 wt %; at least about 30 wt %; atleast about 40 wt %; at least about 50 wt %; or at least about 60 wt %.

In some embodiments, there are provided vehicles and foam formulationsin which the hydrophobic wax is a combination of liquid wax and solidwax where the solid wax is at least about 7 wt %; at least about 10 wt%; at least about 20 wt %; at least about 30 wt %; or at least about 40wt %.

In some embodiments, there are provided vehicles and foam formulationsin which there is a high level of fatty acids. For example, in someembodiments the fatty acids are in excess of about 30%; in excess ofabout 40%; in excess of about 50%; or in excess of about 60% by weightof the formulation.

In some embodiments, there are provided vehicles and foam formulationsin which there is a high level of fatty acids and fatty alcoholscombined. For example, in some embodiments, the fatty acids and fattyalcohols are in excess of about 35%; in excess of about 37%; in excessof about 40% in excess of about 50%; and in excess of about 60%; byweight of the formulation.

In some embodiments, there are provided vehicles and foam formulationsin which there is a high level of fatty acids and or fatty acids andfatty alcohols combined together with a non basic active agent (e.g., aneutral active agent or an acidic active agent). For example, in someembodiments, the fatty acids alone or combined with fatty alcohols arein excess of about 30%; in excess of about 35%; in excess of about 40%;in excess of about 50%; and in excess of about 60%; by weight of theformulation. By “non basic active agent” is meant an active agent thatwhen present in a therapeutically effective amount does not cause asignificant amount of neutralization of an acid formulation. Bysignificant is intended to be about 20% or more neutralization.

In some embodiments, there are provided vehicles and foam formulationsin which there is a high level of fatty acids alone or fatty acids andfatty alcohols combined wherein one of the fatty acids is solid and thepresence of liquid wax enables the solid wax to solubilize at highconcentrations. For example, in some embodiments, the fatty acids andfatty alcohols are in excess of about 37%; in excess of about 40%; inexcess of about 50%; or in excess of about 60% by weight of theformulation.

In some embodiments, there are provided vehicles and foam formulationsin which the amount of jojoba oil is more than 10% by weight of theformulation.

In some embodiments, there are provided vehicles and foam formulationsin which the wax, stabilizer and water and amounts thereof generate anemulsion that is substantially resistant to phase reversal.

In some embodiments, there are provided vehicles and foam formulationsin which the polymer or the polymeric agent is a polymeric surfactant.

In one or more embodiments any of the vehicles and foam formulationsdescribed herein also include an active agent. In some embodiments theformulations include at least one other active agent (i.e., two or moreactive agents in the composition).

In some embodiments, there is also provided a formulation of any of thecompositions described above wherein the composition is in a non foamstate.

In some embodiments, there is also provided a formulation of any of thecompositions described above for use in the manufacture of a medicament.

In one aspect, a method of treating, ameliorating or preventing adisorder of a mammalian subject is provided. The method includesadministering any of the compositions described herein to a target site.

DETAILED DESCRIPTION

The present invention relates to an aqueous composition comprising waxfor use as vehicle, therapeutic, cosmetic or pharmaceutical composition.

According to one or more embodiments, the composition includes:

a pharmaceutical or cosmetic vehicle composition comprising:

-   -   a. at least one hydrophobic wax selected from the group        consisting of a liquid wax, a solid wax and mixtures thereof;    -   b. at least one stabilizer selected from the group consisting of        a surface-active agent, a polymeric agent and mixtures thereof;        and    -   c. water,

wherein the vehicle is substantially free from crystals and issubstantially flowable.

According to one or more embodiments, the hydrophobic wax comprises aliquid wax and a solid wax, wherein the liquid wax concentration inrelation to the solid wax concentration is effective to dissolve anysolid wax crystals in the composition. In an embodiment the compositionfurther comprises a liquefied hydrocarbon gas propellant, wherein theratio of the wax, the stabilizer and water to the gas propellant isabout 100:3 by weight to about 100:35 by weight, wherein upon releasefrom a pressurized container the composition expands to form a breakablefoam.

According to one or more embodiments, the composition includes: afoamable composition comprising:

a. a liquid wax comprising at least one fatty acid or at least one fattyalcohol;b. a stabilizer component comprising a non ionic surface-active agent, apolymeric agent or a mixture thereof;c. water; andd. a liquefied hydrocarbon gas propellant, wherein the ratio of theliquid wax, the stabilizer and water to the gas propellant is about100:3 by weight to about 100:35 by weight;wherein, when the liquid wax comprises at least one fatty acid, thefatty acid is present in the composition at a concentration of at leastabout 35% by weight and wherein, when the liquid wax comprises at leastone fatty alcohol, the fatty alcohol is present in the composition at aconcentration of at least about 12% by weight;wherein the composition is substantially free from crystals and issubstantially flowable;wherein, when the stabilizer component comprises a polymeric agent, thepolymeric agent is present in the vehicle composition at a concentrationof about 0.01% to about 5% by weight and includes a bioadhesive agent, agelling agent, a film forming agent and a phase change agent; andwherein, upon release from a pressurized container, the foam produced isbreakable.

In an embodiment the composition further comprises a solid wax.

According to one or more embodiments, the composition includes: afoamable composition comprising

a. at least about 7% by weight of a solid wax;b. a liquid wax wherein the liquid wax comprises at least one fatty acidor at least one fatty alcoholc. a stabilizer comprising a non ionic surface-active agent, a polymericagent or a mixture thereof;d. water; ande. a liquefied hydrocarbon gas propellant, wherein the ratio of thesolid wax, the liquid wax, the stabilizer and water to the gaspropellant is about 100:3 by weight to about 100:35 by weight;wherein the composition is substantially free from crystals and issubstantially flowable;wherein, when the stabilizer component comprises a polymeric agent, thepolymeric agent is present in the vehicle composition at a concentrationof about 0.01% to about 5% by weight and includes a bioadhesive agent, agelling agent, a film forming agent and a phase change agent; andwherein, upon release from a pressurized container, the foam produced isbreakable.

In one or more embodiments when the composition comprises at least oneliquid fatty acid, the liquid fatty acid is present in the compositionat a concentration of at least about 35% by weight and when thecomposition comprises at least one liquid fatty alcohol, the liquidfatty alcohol is present in the composition at a concentration at leastabout 12% by weight.

According to one or more embodiments, the polymeric agent is about 0.01%to about 5% by weight and is selected from the group consisting of abioadhesive agent, a gelling agent, a film forming agent and a phasechange agent;

According to one or more embodiments, the wax, stabilizer and water areselected to provide a composition that satisfies one, two, three, fouror all of the following

a) substantially resistant to aging;

b) substantially resistant to phase separation;

c) substantially resistant to phase reversal;

d) can substantially stabilize or solubilize active ingredients; or

e) can improve skin penetration.

In one embodiment a) to e) above are satisfied.

In one or more embodiments the composition is contained in a pressurizedcontainer and further comprises a liquefied hydrocarbon gas propellant.In one or more embodiments, the composition provides a foam uponrelease. In one or more embodiments, the composition and/or the foam issubstantially flowable. In some embodiments, the wax, stabilizer,solvent and propellant are selected to generate a breakable foam of goodto excellent quality.

In one embodiment the propellant is added to the total amount ofcomposition, wherein the ratio of the components comprising hydrophobiccomponent, the stabilizer and water to the gas propellant is about 100:3by weight to about 100:35 by weight. In another embodiment the ratio ofthe components comprising hydrophobic component, the stabilizer andwater to the gas propellant is about 100:5 by weight to about 100:25 byweight; or about 100:7 by weight to about 100:20 by weight.

In one or more embodiments there is provided a composition wherein thehydrophobic wax is at a concentration of at least about 30 wt %; 35 wt %37 wt %; 40 wt %; 45 wt %; 50 wt %; 55 wt %; or 60 wt %.

In one or more embodiments there is provided a composition in which thehydrophobic wax includes at least one liquid wax present at aconcentration of at least about 20 wt % and the composition issubstantially free of crystals, wherein the at least one liquid waxcomprises a fatty alcohol. In some embodiments, the fatty alcohol is atleast about 7.5 wt %; 10 wt %; 12 wt %; or 15 wt % of the composition.

In one or more embodiments there is provided a composition in which thehydrophobic wax includes at least one liquid wax present at aconcentration of at least about 30 wt % and the composition issubstantially free of crystals, wherein the at least one liquid waxcomprises a fatty alcohol. In an alternative embodiment the at least oneliquid wax comprises a fatty acid. In some embodiments, the fattyalcohol is at least about 7.5 wt %; 10 wt %; 12 wt %; 15 wt %; 20 wt %;or 25 wt % of the composition.

In one or more embodiments there is provided a composition in which thehydrophobic wax includes at least one liquid wax present at aconcentration of at least about 35 wt % and the composition issubstantially free of crystals, wherein the at least one liquid waxcomprises a fatty alcohol. In an alternative embodiment the at least oneliquid wax comprises a fatty acid. In some embodiments, the fattyalcohol is at least about 7.5 wt %; 10 wt %; 12 wt %; 15 wt %; 20 wt %;25 wt %; or 30 wt %. of the composition

In one or more embodiments there is provided a composition in which thehydrophobic wax includes at least one liquid wax present at aconcentration of at least about 40% by weight and the composition issubstantially free of crystals wherein the at least one liquid waxcomprises a fatty alcohol. In an alternative embodiment the at least oneliquid wax comprises a fatty acid. In some embodiments, the fattyalcohol is at least about 7.5 wt %; 10 wt %; 12 wt %; 15 wt %; 20 wt %;25 wt %; 30 wt % or 35 wt % of the composition.

In one or more further embodiments the liquid wax is at least about 45wt %; and the fatty alcohol comprises at least about 7.5 wt %; 10 wt %;15 wt %; 20 wt %; 25 wt %; 30 wt %; 35 wt % or 40 wt %; or the liquidwax is at least about 50 wt %; and the fatty alcohol comprises at leastabout 7.5 wt %; 10 wt %; 15 wt %; 20 wt %; 25 wt %; 30 wt %; 35 wt %; 40wt %; or 45 wt % or the liquid wax is at least about 55 wt %; and thefatty alcohol comprises at least about 7.5 wt %; 10 wt %; 15 wt %; 20 wt%; 25 wt %; 30 wt %; 35 wt %; 40 wt %; 45 wt %; 50 wt % or the liquidwax comprises at least about 60 wt %; and the fatty alcohol comprises atleast about 7.5 wt %; 10 wt %; 12 wt %; 15 wt %; 20 wt %; 25 wt %; 30 wt%; 35 wt %; 40 wt %; 45 wt %; 50 wt %; or 55 wt %.

In one or more embodiments there is provided a composition in which thehydrophobic wax includes at least one liquid wax present at aconcentration of at least about 30%, about 35% about 40% or about 45% byweight and the composition is substantially free of crystals and issubstantially flowable.

In one or more embodiments there is provided a composition in which thehydrophobic wax present in the composition includes at least one solidwax and at least one liquid wax, wherein the liquid wax is at aconcentration of at least about 20 wt %; 25 wt %; 30 wt %; 35 wt % 37 wt%; 40 wt %; 45 wt %; 50 wt %; 55 wt %; or 60 wt % by weight and thecomposition is substantially free of crystals.

In one or more embodiments there is provided a composition in which thehydrophobic wax present in the composition is at a concentration of atleast about 40% by weight and comprises at least one solid wax and thecomposition is substantially free of crystals.

In one or more embodiments there is provided a composition in which thehydrophobic wax comprises at least one liquid wax and at least one solidwax present at a concentration of at least about 40% by weight and thecomposition is substantially free of crystals, wherein the liquid wax isa fatty acid.

In one or more embodiments there is provided a composition in which thehydrophobic wax present in the composition comprises at least about 7 wt% of at least one solid wax and at least one liquid wax, and thecomposition is substantially free of crystals. In some embodiments, thesolid wax is at a concentration of at least about 7.5 wt %; 10 wt %; 15wt %; 20 wt %; 25 wt %; 30 wt %; 35 wt % or 40 wt %. In a furtherembodiment where the solid wax is at least about 7% or more the liquidwax is at a concentration of at least about 7.5 wt %; 10 wt %; 15 wt %;20 wt %; 25 wt %; 30 wt %; 35 wt % or 40 wt %.

In one or more embodiments there is provided a composition substantiallyfree of crystals, wherein the hydrophobic wax comprises at least oneliquid wax and at least one solid wax present at a concentration of atleast about 36% by weight, wherein the amount of solid wax is at leastabout 8% or wherein the ratio of liquid wax to solid wax is betweenabout 9:2 to about 1:6. For example, in one embodiment, the amount ofhydrophobic wax is about 36% and the amount of solid wax is at leastabout 8% and the amount of liquid wax is about 28%. Similarly, in oneembodiment the amount of solid wax is about 10% and the amount of liquidwax is 26%. Likewise, if the amount of hydrophobic wax is about 38% andthe amount of solid wax is about at least 8% then the liquid wax isabout 30%. Similarly, if the amount of solid wax is about 10% the amountof liquid wax is 28% and so on. More particularly the ratio of liquidwax to solid was is about 9:2; about 4:1; about 3:1; about 2:1; about1:1; about 1:2; about 1:3; about 1:4 about 1:5 or about 1:6 or anythingin between these ratios.

In one or more embodiments the ratio of fatty alcohol to fatty acid isbetween about 10:9 to about 8:1

In one or more embodiments the ratio of liquid wax to solid wax isbetween about 10:1 to about 1:10. In one or more other embodiments theratio of liquid wax to solid wax is between about 5:1 to about 1:5. Inone or more further embodiments the ratio of liquid wax to solid wax isbetween about 1:1 to about 3:1. Alternatively in one or more embodimentsthe ratio of liquid wax to solid wax is between about 3:1 to about 1:1.

In one or more embodiments there is provided a composition in which thehydrophobic wax includes at least one liquid wax, wherein the liquid waxcomprises at least about 10% jojoba oil.

In one or more embodiments there is provided a composition in which thehydrophobic wax comprises at least one liquid wax present at aconcentration of at least about 20% by weight, wherein the liquid waxcomprises at least about 10% jojoba oil;

In one or more embodiments there is provided a composition in which thehydrophobic wax comprises at least one liquid wax present at aconcentration of at least about 30% by weight, wherein the liquid waxcomprises at least about 20% jojoba oil.

In one or more embodiments there is provided a composition in which thehydrophobic wax comprises at least about 20% jojoba oil; at least about30% jojoba oil; at least about 40% jojoba oil; at least about 50% jojobaoil; at least about 60% jojoba oil; or at least about 70% jojoba oil;

In one or more embodiments there is provided a composition in which thehydrophobic wax combination comprises solid wax at a concentration ofabout 30 wt % or more and the composition is substantially free ofcrystals.

In one or more embodiments there is provided a composition in which thesolid wax is at a concentration of about or less than 37 wt %. In one ormore embodiments the compositions described herein further include anactive agent.

In an embodiment the active agent is soluble in the composition at anacidic pH. In another embodiment the active agent is non basic or doesnot cause significant neutralization of the composition. In anembodiment the active agent is solubilized by first dissolving theactive agent directly in organic hydrophobic liquid wax or an organicwax or a combination thereof.

In one or more embodiments the compositions described herein include asolvent. Exemplary solvents include, without limitation an organiccarrier, a hydrophilic solvent; a hydrophobic solvent; a potent solvent;a polar solvent, a silicone, an emollient, and mixtures thereof.

In one or more embodiments there is provided a composition, wherein thewax, stabilizer and water are selected to generate a surfactant layer orinterphase with substantially organized chaos.

In one or more embodiments there is provided a composition, wherein thebreakable foam comprises a micro or nano emulsion.

In one or more embodiments there is provided a composition, which issubstantially resistant to one or more Freeze-Thaw cycles (FTC).

In one or more embodiments the surface-active agent is a solid, a liquidor a mixture thereof.

Exemplary surface active agents for use in the compositions describedherein include a polysorbate, polyoxyethylene (20) sorbitanmonostearate, polyoxyethylene (20) sorbitan monooleate, apolyoxyethylene fatty acid ester, Myrj 45, Myrj 49, Myrj 52, Myrj 59, apolyoxyethylene alkynyl ether, polyoxyethylene cetyl ether,polyoxyethylene palmityl ether, polyethylene oxide hexadecyl ether,polyethylene glycol cetyl ether, brij 38, brij 52, brij 56 and brij W1,a sucrose ester, a partial ester of sorbitol, sorbitan monolaurate,sorbitan monolaurate a monoglyceride, a diglyceride, isoceteth-20, asucrose ester, steareth 2, glyceryl monostearate/PEG 100 stearate,Glyceryl Stearate, Steareth-21, peg 40 stearate, polysorbate 60,polysorbate 80, sorbitan stearate, laureth 4, Sorbitan monooleate,ceteareth 20, steareth 20, ceteth 20, Macrogol Cetostearyl Ether, ceteth2, PEG-30 Dipolyhydroxystearate, sucrose distearate, polyoxyethylene(100) stearate, PEG 100 stearate, PEG 40 stearate, laureth 4,cetomacrogol ether, Cetearyl alcohol, Cetearyl glucoside, Oleyl alcohol,Steareth-2, Diisopropyl adipate, Capric/caprilic triglicerides,Polysorbate 20; Montanov 68 (CETEARYL ALCOHOL (and) CETEARYLGLUCOSIDE.), Sharonmix 824 (a liquid blend of methyl paraben, ethylparaben and propyl paraben—in phenoxyethanol), Simusol 165 (Glycerylstearate and PEG-100 stearate). Methyl glucose sequistearate, Peg 30dipolyhydroxystearate, sucrose stearic acid esters, sorbitan laureth,sorbitan stearate and mixtures thereof.

In one or more embodiments there is provided a composition, wherein thesurface active agent comprises a polysorbate.

In one or more embodiments there is provided a composition, wherein thesurface active agent comprises PEG 30 dipolyhydroxysearate.

In one or more embodiments there is provided a composition, wherein thesurface active agent also functions as a solvent.

In one or more embodiments there is provided a composition, wherein thepolymeric agent is selected from the group consisting of carbopol 934,pemulen TR2, klucel EF, xanthan gum, methocel A4M, and carboxy methylcellulose or selected from the group consisting of locust bean gum,sodium alginate, sodium caseinate, egg albumin, gelatin agar,carrageenin gum, sodium alginate, xanthan gum, quince seed extract,tragacanth gum, guar gum, cationic guars, hydroxypropyl guar gum,starch, an amine-bearing polymer, chitosan, alginic acid, hyaluronicacid, a chemically modified starch, a carboxyvinyl polymer,polyvinylpyrrolidone, polyvinyl alcohol, a polyacrylic acid polymer, apolymethacrylic acid polymer, polyvinyl acetate, a polyvinyl chloridepolymer, a polyvinylidene chloride polymer, methylcellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxy propylmethyl cellulose, methylhydroxyethylcellulose,methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose,carboxymethyl cellulose, carboxymethylcellulosecarboxymethylhydroxyethylcellulose, a cationic cellulose, aluminumstarch octenylsuccinate (ASOS), sodium starch octenylsuccinate, PEG1000, PEG 4000, PEG 6000 and PEG 8000.

In one or more embodiments there is provided a composition, wherein thepolymeric agent is a derivatized polymeric emulsifier. In one or otherembodiments the polymer is a polymeric surfactant. Non limiting examplesare a poloxamer or a pemulen.

The foamable composition can be an emulsion, or microemulsion, includingan aqueous phase and an organic carrier phase, which comprises at leastone hydrophobic solvent, which is a wax, selected from the groupconsisting of (1) a fatty alcohol; (2) a fatty acid; and (3) certainnaturally occurring waxes. The wax, according to the present inventionis hydrophobic. A “hydrophobic solvent” as used herein refers to amaterial having solubility in distilled water at ambient temperature ofless than about 1 gm per 100 mL, in some embodiments less than about 0.5gm per 100 mL, and in other embodiments less than about 0.1 gm per 100mL. It is semi-solid or liquid at ambient temperature. Theidentification of a “hydrophobic solvent”, as used herein, is notintended to characterize the solubilization capabilities of such solventfor any specific active agent or any other component of the foamablecomposition. Rather, such information is provided to aid in theidentification of materials suitable for use as a hydrophobic componentin the foamable compositions described herein.

Examples of waxes, suitable as hydrophobic solvents in accordance to thepresent invention include, but are not limited, to the following:

In one or more embodiments there is provided a composition, wherein thewax is a C8 to C22 fatty acid or fatty alcohol.

In one or more embodiments there is provided a composition, wherein thewax is a C16 to C20 fatty acid or fatty alcohol.

In one or more embodiments there is provided a composition, wherein thewax is a branched chain fatty acid or fatty alcohol.

In one or more embodiments there is provided a composition, wherein thewax is a straight chain fatty acid or fatty alcohol.

In one or more embodiments there is provided a composition, wherein thewax is a saturated fatty acid or fatty alcohol.

In one or more embodiments there is provided a composition, wherein thewax is an unsaturated fatty acid or fatty alcohol.

In one or more embodiments there is provided a composition, wherein thewax is selected from the group consisting of isostearic acid, oleicacid, oleyl alcohol, stearic acid, cetyl alcohol, stearyl alcohol,erucic acid, linoleic acid, arachidonic acid and linolenic acid.

In one or more embodiments there is provided a composition, wherein thewax is selected from the group consisting of. lauric acid, myristicacid, palmitic acid, stearic acid, behenic acid, oleic acid,12-hydroxystearic acid, undecylenic acid, tall acid, isostearic acid,linoleic acid, linolenic acid, eicosapentaenoic acid (EPA),docosahexaenoic acid (DHA), and an equivalent fatty alcohol thereof.

In one or more embodiments there is provided a composition, wherein thewax is selected from the group consisting of animal waxes, spermaceti,lanolin (wool wax), insect waxes, beeswax, chinese wax, vegetable waxes,candelilla wax, castor wax, jojoba oil, rice bran wax; petroleum waxes,paraffin waxes, microcrystalline wax; synthetic waxes, polyethylenewaxes, Fischer-Tropsch waxes, chemically modified and substituted waxes;and mineral waxes.

In one or more embodiments there is provided a composition, wherein thewax is selected from the group consisting of coconut oil, palm oil,tallow and jojoba oil.

In one or more embodiments there is provided a composition, wherein thewax is jojoba oil.

In one or more embodiments there is provided a composition furthercomprising an additional active agent.

In one or more embodiments there is provided a composition, furthercontaining a foam adjuvant. In one or more embodiments certainhydrophobic waxes can function as a foam adjuvant. Solid hydrophobicwaxes are preferred. Thus, In addition to the hydrophobic wax acting asthe main “oil” phase it can contribute to the foam stability andquality. Mixtures of solid wax with liquid wax can be ideal where forexample, depending on the actual ingredients used, a solid wax primarilyacts as the adjuvant and a liquid wax as the solvent and co adjuvant.

In one or more embodiments there is provided a composition furthercontaining at least one organic carrier (other than wax) selected fromthe group consisting of a hydrophobic organic carrier, an emollient andmixtures thereof, at a concentration of about 2% to about 50% by weight.

In one or more embodiments there is provided a composition, wherein theorganic carrier is selected from the group consisting of mineral oil,triglycerides, medium chain triglyceride (MCT) oil, capric/caprylictriglyceride, alkyl esters of fatty acids such as isopropyl palmitate,isopropyl myristate, isopropyl isostearate, poly propylene glycol15-stearly ether, octyl palmitate, cetyl lactate, cetyl ricinoleate,tocopheryl acetate, acetylated lanolin alcohol, cetyl acetate, phenyltrimethicone, glyceryl oleate, tocopheryl linoleate, wheat germglycerides, arachidyl propionate, myristyl lactate, decyl oleate,ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate,neopentylglycol dicaprylate/dicaprate, isononyl isononanoate,isotridecyl isononanoate, myristyl myristate, triisocetyl citrate, octyldodecanol, maleated soybean oil, unsaturated or polyunsaturated oils,such as olive oil, corn oil, soybean oil, canola oil, cottonseed oil,coconut oil, sesame oil, sunflower oil, borage seed oil, syzigiumaromaticum oil, hempseed oil, herring oil, cod-liver oil, salmon oil,flaxseed oil, wheat germ oil, evening primrose oils; essential oils; andsilicone oils, such as dimethicone, cyclomethicone, polyalkyl siloxane,polyaryl siloxane, polyalkylaryl siloxane, a polyether siloxanecopolymer and a poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer anda polypropylene glycol alkyl ether.

In one or more embodiments there is provided a composition furthercontaining at least one polar solvent.

In one or more embodiments there is provided a composition, wherein thepolar solvent is selected from the group consisting of dimethylisosorbide, glycerol, propylene glycol, hexylene glycol, diethyleneglycol, propylene glycol n-alkanols, terpenes, di-terpenes,tri-terpenes, limonene, terpene-ol, 1-menthol, dioxolane, ethyleneglycol, other glycols, oleyl alcohol, alpha-hydroxy acids, such aslactic acid and glycolic acid, sulfoxides, such as dimethylsulfoxide(DMSO), dimethylformanide, methyl dodecyl sulfoxide, dimethylacetamide,azone (1-dodecylazacycloheptan-2-one), 2-(n-nonyl)-1,3-dioxolane,alkanols, such as dialkylamino acetates, and admixtures thereof.

In one or more embodiments there is provided a composition, wherein theorganic carrier is capric/caprylic triglyceride.

In one or more embodiments there is provided a composition, wherein thewax, stabilizer and water are selected to generate an emulsion that canproduce a substantially strong and closed packed barrier between the oiland the water phases whilst maintaining a fluid constitution and asurfactant layer or interphase with substantially organized chaos.

In one or more embodiments there is provided a composition, furthercomprising an additional component selected from the group consisting ofa modulating agent, a polar solvent, an anti perspirant, an anti-staticagent, a buffering agent, a bulking agent, a chelating agent, acolorant, a conditioner, a deodorant, a diluent, a dye, an emollient,fragrance, a humectant, an occlusive agent, a penetration enhancer, aperfuming agent, a permeation enhancer, a pH-adjusting agent, apreservative, a skin penetration enhancer, a sunscreen, a sun blockingagent, a sunless tanning agent, and a vitamin.

In one or more embodiments there is provided a therapeutic orpharmaceutical composition comprising:

-   -   i. at least one hydrophobic wax selected from the group        consisting of a liquid wax, a solid wax and mixtures thereof;    -   ii. at least one stabilizer selected from the group consisting        of a surface-active agent, a polymeric agent and mixtures        thereof;    -   iii. water;    -   iv. an active agent; and    -   v. a liquefied hydrocarbon gas propellant, wherein the ratio of        the solid wax, the liquid wax, the stabilizer and water to the        gas propellant is about 100:3 by weight to about 100:35 by        weight;

wherein the vehicle is substantially free from crystals, issubstantially flowable and upon release from a pressurized containerprovides a breakable foam.

The term therapeutic composition includes pharmaceutical composition andboth these terms can be used interchangeably.

In an embodiment where the pharmaceutical composition comprises a liquidwax and a solid wax, the stabilizer comprises about 1% to about 5% of atleast one surface-active agent and about 1% to about 5% of at least onepolymeric agent.

In one or more embodiments there is provided a therapeutic composition,wherein the active agent is selected from the group consisting of activeherbal extracts, acaricides, age spot and keratose removing agents,allergen, analgesics, local anesthetics, antiacne agents, antiallergicagents, antiaging agents, antibacterials, antibiotics, antiburn agents,anticancer agents, antidandruff agents, antidepressants, antidermatitisagents, antiedemics, antihistamines, antihelminths, antihyperkeratolyteagents, antiinflammatory agents, antiirritants, antilipemics,antimicrobials, antimycotics, antiproliferative agents, antioxidants,anti-wrinkle agents, antipruritics, antipsoriatic agents, antirosaceaagents antiseborrheic agents, antiseptic, antiswelling agents, antiviralagents, antiyeast agents, antiwart agents, astringents, topicalcardiovascular agents, chemotherapeutic agents, corticosteroids,dicarboxylic acids, disinfectants, fungicides, hair growth regulators,hormones, hydroxy acids, immunosuppressants, immunoregulating agents,insecticides, insect repellents, keratolytic agents, lactams, metals,metal oxides, mitocides, neuropeptides, steroids, non-steroidalanti-inflammatory agents, oxidizing agents, pediculicides, photodynamictherapy agents, retinoids, sanatives, scabicides, self tanning agents,skin whitening agents, vasoconstrictors, vasodilators, vitamins, vitaminD derivatives, wound healing agents and wart removers as well as agentshaving activity against superficial basal cell carcinomas, actinickeratoses, Bowen's disease and or other squamous cell carcinomas andmolluscum contagiosum.

In one or more embodiments there is provided a therapeutic composition,wherein the wax is present in the composition in an amount sufficient tosolubilize the active agent.

In one or more embodiments there is provided a therapeutic composition,wherein the active agent is selected from the group consisting of atleast one of imiquimod, resiquimod, gardiquimod, an interferon, animmunomodulator, podophyllin (anti-mitotic), podofilox, 5-fluorouracil(5-FU), and trichloroacetic acid (TCA), fluorouracil, afovirsen, inosinepranobex, podophyllum, trichloroacetic acid, thiotep, diclofenac,5-aminolevulinic acid and derivatives, tretinoin, a cyclic peptide,cyclosporine, tacrolimus, tresperimus, pimecrolimus, sirolimus,verolimus, laflunimus and laquinimod.

In one or more embodiments there is provided a therapeutic composition,wherein the active agent is imiquimod.

In one or more embodiments there is provided a therapeutic composition,wherein the active agent is used against herpes simplex virusinfections, other viral infections and eczema and as a vaccine adjuvant.

In one or more embodiments there is provided a therapeutic composition,wherein imiquimod is used in combination with at least one of the groupconsisting of meglumine antimoniate; cryotherapy; acyclovir;5-aminolevulinic acid; fluorouracil; salicylic acid a COX inhibitor andsulindac.

In one or more embodiments there is provided a therapeutic composition,wherein the active agent is a steroid.

In one or more embodiments there is provided a therapeutic composition,wherein the steroid is selected from the group consisting ofbydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone,dexamethasone-phosphate, beclomethsone dipropionate, clobetasolvalemate, desonide, desoxymethasone, desoxycorticosterone acetate,dexamethasone, dichlorisone, diflorasone diacetate, diflucortolonevalerate, fluadrenolone, fluclorolone acetonide, fludrocortisone,flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortinebutylester, fluocortolone, fluprednidene (fluprednylidene) acetate,flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisonebutyrate, methylprednisolone, triamcinolone acetonide, cortisone,cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate,fluradrenolone acetonide, medrysone, amcinafel, amcinafide,betamethasone and the balance of its esters, chloroprednisone,chlorprednisone acetate, clocortelone, clescinolone, dichlorisone,difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone,fluprednisolone, hydrocortisone valerate, hydrocortisonecyclopentylpropionate, hydrocortmate, mepreddisone, paramethasone,prednisolone, prednisone, beclomethasone dipropionate, andtriamcinolone.

In one or more embodiments there is provided a therapeutic composition,wherein the active agent is an immunomodulator.

In one or more embodiments there is provided a therapeutic composition,wherein the immunomodulator is selected from the group consisting of acyclic peptide, cyclosporine, tacrolimus, tresperimus, pimecrolimus,sirolimus, verolimus, laflunimus, laquinimod and imiquimod.

In one or more embodiments there is provided a therapeutic composition,wherein the wax is present in the composition in an amount sufficient tosolubilize the immunomodulator.

In one or more embodiments there is provided a therapeutic composition,wherein the composition further comprises a solvent selected from thegroup consisting of an organic carrier, a hydrophilic solvent; ahydrophobic solvent; a potent solvent; a polar solvent, a silicone, anemollient, and mixtures thereof.

In one or more embodiments there is provided a therapeutic composition,wherein the wax, stabilizer and water are selected to generate anemulsion that is substantially resistant to phase reversal.

In one or more embodiments there is provided a therapeutic composition,wherein the wax, stabilizer and water are selected to generate asurfactant layer or interphase with substantially organized chaos.

In one or more embodiments there is provided a method of treating,ameliorating or preventing a disorder of a mammalian subject,comprising: administering a foamable therapeutic composition to a targetsite, the composition comprising:

-   a. a therapeutically effective amount of an active agent;-   b. at least one hydrophobic wax selected from the group consisting    of a liquid wax, a solid wax and mixtures thereof;-   c. at least one stabilizer selected from the group consisting of a    surface-active agent, a polymeric agent and mixtures thereof; and-   d. water;-   e. a liquefied hydrocarbon gas propellant, wherein the ratio of the    solid wax, the liquid wax, the stabilizer and water to the gas    propellant is about 100:3 by weight to about 100:35 by weight;    wherein the vehicle is substantially free from crystals, is    substantially flowable and upon release from a pressurized container    provides a breakable foam.

In one or more embodiments there is provided a method of treating,wherein the composition is contained in a pressurized container andfurther comprises a liquefied hydrocarbon gas propellant at aconcentration of about 3% to about 35% by weight of the totalcomposition, is substantially flowable and provides a foam upon releaseand wherein the wax, stabilizer and water are selected to generate abreakable foam of good to excellent quality.

In one or more embodiments there is provided a method of treating,wherein the target site is selected from the group consisting of theskin, a body cavity, a mucosal surface, the nose, the mouth, the earcanal, the vagina and the rectum.

In one or more embodiments there is provided a method of treating,wherein the disorder is selected from the group consisting ofdermatological pain, dermatological inflammation, acne, acne vulgaris,inflammatory acne, non-inflammatory acne, acne fulminans, nodularpapulopustular acne, acne conglobata, dermatitis, bacterial skininfections, fungal skin infections, viral skin infections, parasiticskin infections, skin neoplasia, skin neoplasms, pruritis, cellulitis,acute lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses,necrotizing subcutaneous infections, scalded skin syndrome,folliculitis, furuncles, hidradenitis suppurativa, carbuncles,paronychial infections, rashes, erythrasma, impetigo, ecthyma, yeastskin infections, warts, molluscum contagiosum, trauma or injury to theskin, post-operative or post-surgical skin conditions, scabies,pediculosis, creeping eruption, eczemas, psoriasis, pityriasis rosea,lichen planus, pityriasis rubra pilaris, edematous, erythema multiforme,erythema nodosum, granuloma annulare, epidermal necrolysis, sunburn,photosensitivity, pemphigus, bullous pemphigoid, dermatitisherpetiformis, keratosis pilaris, callouses, corns, ichthyosis, skinulcers, ischemic necrosis, miliaria, hyperhidrosis, moles, Kaposi'ssarcoma, melanoma, malignant melanoma, basal cell carcinoma, squamouscell carcinoma, poison ivy, poison oak, contact dermatitis, atopicdermatitis, rosacea, purpura, moniliasis, candidiasis, baldness,alopecia, Behcet's syndrome, cholesteatoma, Dercum disease, ectodermaldysplasia, gustatory sweating, nail patella syndrome, lupus, hives, hairloss, Hailey-Hailey disease, chemical or thermal skin burns,scleroderma, aging skin, wrinkles, sun spots, necrotizing fasciitis,necrotizing myositis, gangrene, scarring, and vitiligo; and wherein theactive agent is suitable for treating said disorderm or is selected fromthe group consisting of chlamydia infection, gonorrhea infection,hepatitis B, herpes, HIV/AIDS, human papillomavirus (HPV), genitalwarts, bacterial vaginosis, candidiasis, chancroid, granuloma Inguinale,lymphogranuloma venereum, mucopurulent cervicitis (MPC), molluscumcontagiosum, nongonococcal urethritis (NGU), trichomoniasis, vulvardisorders, vulvodynia, vulvar pain, yeast infection, vulvar dystrophy,vulvar intraepithelial neoplasia (VIN), contact dermatitis, pelvicinflammation, endometritis, salpingitis, oophoritis, genital cancer,cancer of the cervix, cancer of the vulva, cancer of the vagina, vaginaldryness, dyspareunia, anal and rectal disease, anal abscess/fistula,anal cancer, anal fissure, anal warts, Crohn's disease, hemorrhoids,anal itch, pruritus ani, fecal incontinence, constipation, polyps of thecolon and rectum; warts; herpes simplex virus infections, other viralinfections, superficial basal cell carcinomas, actinic keratoses,Bowen's disease and/or other squamous cell carcinomas, molluscumcontagiosum and eczema, and wherein the active agent is suitable fortreating said disorder.

In one or more embodiments there is provided a method of treating,wherein the disorder is a dermatological disorder, which can be treated,ameliorated or prevented by a topical steroid, an immunomodulator or ananti-infective agent.

In one or more embodiments there is provided a method of treating,wherein the active agent is selected from the group consisting ofimiquimod, resiquimod, gardiquimod, an interferon, an immunomodulator,podophyllin (anti-mitotic), podofilox, 5-fluorouracil (5-FU), andtrichloroacetic acid (TCA), fluorouracil, afovirsen, inosine pranobex,podophyllum, trichloroacetic acid, thiotep, diclofenac, 5-aminolevulinicacid and derivatives, tretinoin, a cyclic peptide, cyclosporine,tacrolimus, tresperimus, pimecrolimus, sirolimus, verolimus, laflunimusand laquinimod.

In one or more embodiments there is provided a pharmaceuticalcomposition, further comprising an additional component selected fromthe group consisting of a modulating agent, a polar solvent, an antiperspirant, an anti-static agent, a buffering agent, a bulking agent, achelating agent, a colorant, a conditioner, a deodorant, a diluent, adye, an emollient, fragrance, a humectant, a moisturizer, an occlusiveagent, a penetration enhancer, a perfuming agent, a permeation enhancer,a pH-adjusting agent, a preservative, a skin penetration enhancer, asunscreen, a sun blocking agent, a sunless tanning agent,

In one or more embodiments there is provided a pharmaceuticalcomposition comprising:

-   -   i. a liquid wax selected from the group consisting of isostearic        acid, oleyl alcohol, octyldodecanol, isostearyl alcohol and        jojoba oil;    -   ii. a stabilizer comprising about 1% to about 5% of at least one        surface-active agent comprising a liquid surfactant and about        0.1% to about 5% of at least one polymeric agent;    -   iii. water; and    -   iv. an active agent,        wherein the composition is substantially free from crystals, is        substantially flowable and upon release from a pressurized        container provides a breakable foam;        wherein the liquid wax is about 7% to about 70% by weight of the        composition.

In one or more embodiments there is provided a pharmaceuticalcomposition comprising:

-   -   i. a liquid wax selected from the group consisting of isostearic        acid, oleyl alcohol, octyldodecanol, isostearyl alcohol, and        jojoba oil and a solid wax selected from the group consisting of        stearic acid, cetyl alcohol and stearyl alcohol;    -   ii. a stabilizer comprising about 1% to about 5% of at least one        surface-active agent comprising a liquid surfactant and about        0.1% to about 5% of at least one polymeric agent;    -   iii. water; and    -   iv. an active agent,        wherein the vehicle is substantially free from crystals, is        substantially flowable and upon release from a pressurized        container provides a breakable foam.

In one or more embodiments the ranges of an ingredient can be betweenany two figures mentioned for that ingredient.

In one or more embodiments the ranges of a ratio between two substancesA:B can be between any two sets of figures mentioned for that ratio.

In one or more embodiments there is provided a vehicle or a therapeuticor a pharmaceutical composition in a non foam state.

In one or more embodiments there is also provided a formulation of anyof the compositions described herein for use in the manufacture of amedicament.

In one aspect, a method of treating, ameliorating or preventing adisorder of a mammalian subject is provided. The method includesadministering any of the compositions described herein to a target site.

All % values are provided on a weight (w/w) basis.

Wax

In an embodiment, the organic carrier comprises a wax. By wax is meantin the wider sense, waxes, waxy substances, counterparts and derivativesthereof. Waxes may be natural such as beeswax, carnauba and paraffin orartificial. Some artificial materials that exhibit similar propertiesare also described as wax or waxy. Chemically, a wax may be an ester ofethylene glycol (ethan-1,2-diol) and two fatty acids, as opposed to afat which is an ester of glycerin (propan-1,2,3-triol) and three fattyacids. It may also be a combination of other fatty alcohols with fattyacids. Non limiting examples of: animal waxes are spermaceti and lanolin(wool wax); insect waxes are beeswax and chinese wax; vegetable waxesare candelilla wax, castor wax, jojoba oil and rice bran wax; petroleumwaxes are paraffin waxes and microcrystalline wax; synthetic waxes arepolyethylene waxes Fischer-Tropsch waxes, chemically modified andsubstituted waxes; and mineral waxes. Formerly waxes were fatty acidesters with monohydric fatty alcohols having wax like properties,however, the category has been widely extended to include any organicmaterial having wax-like properties. Some typical characteristics ofwaxes are water repellency being hydrophobic, relatively low viscositywhen liquid, and plasticity. In the context herein, a wax can be a solidwax or a liquid wax and includes waxy substances, like fatty acids andtheir fatty alcohol counterparts, which can be short, medium and longchain. The fatty acid or alcohol backbone may be straight, branched,saturated, unsaturated, or hydrogenated, unhydrogenated, natural, orsynthetic. Where one type of backbone produces a waxy substance thenmolecules with the substantially the same backbone are also deemed asbeing part of the wax family or being a waxy substance counterpart orderivative thereof. For example, stearic acid and stearyl alcohol arewaxy solids with a C18 backbone. In other cases, however, where thecarbon backbone chain is also C18, such as isostearic acid, oleic acidand oleyl alcohol, they are liquids but are likewise considered to bewaxy substances, having a commonality with regards to the number ofcarbon atoms in the formula. Also considered within the scope is wherehydrogenation would form a wax or waxy substance. The significance ofthis difference in liquidity of molecules having the same or similarbackbone chain on foamable compositions is investigated herein. Othernon limiting examples of fatty acids and fatty alcohols having acommonality of formula of backbone C chain are shown in Table 1:

TABLE 1 Saturated Solid = S C Formula Unsaturated Solid = S C FormulaFatty Solid = S C Formula Acid Liquid = L Backbone Acid Liquid = LBackbone Alcohol Liquid = L Backbone Butyric L C4:0* Caproic L C6:0Caprylic L C8:0 capryl L C8:0 1-nonanol L C9:0 Capric S C10:0 Capric LC10:0 (strong skin irritant can be harmful) undecanol L C11:0 Lauric SC12:0 1 S C12:0 dodecanol Myristic S C14:0 Myristoleic S C14:1 myristylS C14:0 acid: Palmitic S C16:0 cetyl S C16:0 Palmitoleic L C16:1palmitoleyl C16:1 acid: Stearic S C18:0 Oleic acid: L C18:1 stearyl SC18:0 Isostearic L C18:B isostearyl L C18:B oleyl L C18:1 Linoleic LC18:2 acid: Alpha- L C18:3 linolenic acid: Arachidic S C20:0 ArachidonicL C20:4 arachidyl S C20:0 acid Eicosapenta S C20:5 enoic acid Behenic SC22:0 Erucic acid: S C22:1 behenyl S C22:0 Docosahexa S C22:6 enoic acid*The carbon backbone formula is interpreted as follows: the first numberis the number of carbons in the backbone, while the second number is thedegree of unsaturation (i.e., number of double bonds). Accordingly,C18:0 refers to a 18-carbon straight chain, while C18:1 refers to18-carbon straight chain with one double bond and C18:2 refers to18-carbon straight chain with two double bonds. “B” refers to a branchedchain (i.e., C18:B refers to 18-carbon branced chain).

As will be appreciated only those fatty acids and fatty alcohols thatare suitable for application to the skin, eyes or body cavity may beused in a pharmaceutical or cosmetic formulation. Capric alcohol forexample is known to cause high irritability to skin and eyes and ifsplashed into the eyes it can cause permanent damage and its use can beharmful. Accordingly, it is excluded from the scope herein.

In selecting a wax in order to make a foamable formulation carefulthought must be given not only to whether it is liquid or solid, butalso to its length, its shape and its usability in a therapeuticcomposition. Usability should be looked at both from the aspect of thesuitability for the target to which the formulation is to be applied andalso from the aspect of whether it can act as a destabiliser or defoamerin the proposed formulation.

In an embodiment, one or both of the fatty alcohol and fatty acid are astraight-chain molecules. In another embodiment one or both arebranched. In a further embodiment one or both are saturated and inanother embodiment one or both are unsaturated. When unsaturated one orboth may be cis or trans unsaturated. Further one or both may bepolyunsaturated. In an additional embodiment one or both arehydrogenated and in a different embodiment one or both areunhydrogenated. In an embodiment mixtures of two or more types may becombined.

Additional members are derived from natural products or from synthesis.

As can been seen from Table 1, long, straight chain saturated fattyacids (C10:0 and higher) are solid at room temperature, which does notmake them suitable as solvents and makes them difficult to use in higherconcentrations for foamable formulations and foam despite their usefulproperties. The unsaturated long chain fatty acids like e.g. oleic acidare liquid at room temperature, so they are potentially suitable assolvents and easier to use at higher concentrations, but are potentiallyunstable because of the existence of double bond(s). Branched fattyacids mimic the properties of the straight chain unsaturated fatty acidsin many respects. However, they do not have the disadvantage of beingunstable. For example branched C18:0 fatty acid (commercially known asisostearic acid) is liquid at room temperature, but is not as unstableas its C18:1 unsaturated counterpart, since unsaturated bonds are absentin branched C18:0. Therefore, branched fatty acids are for manyapplications more desirable than straight chain fatty acids. (The term“branched fatty acids” is herein to be understood to comprise fattyacids which contain one or more alkyl side groups, which can be attachedto the carbon chain at any position. Such alkyl groups are generallyshort (e.g., having 1-6 carbon atoms, 1-5 carbon atoms, 1-4 carbonatoms, or 1-3 carbon atoms). Branched fatty acids (and similarlybranched fatty alcohols) due to their irregular shape can be morechaotic than their straight chain counterparts as is explained in moredetail below.

In one or more embodiments the wax, waxy substance, counterpart orderivative thereof is a saturated branched fatty acid or fatty alcohol.

In one embodiment fatty acids which may be used in the fatty acid waxysubstances, counterparts or derivatives include those having an alkyl oralkenyl group having 12 or more carbon atoms, in some embodiments 14 to22 carbon atoms, and in other embodiments 16-22 carbon atoms. Examplesof such fatty acid waxes are fatty acids such as lauric acid, myristicacid, palmitic acid, stearic acid, behenic acid, oleic acid,12-hydroxystearic acid, undecylenic acid, tall acid, isostearic acid,linoleic acid, linolenic acid, eicosapentaenoic acid (EPA),docosahexaenoic acid (DHA), or the equivalent fatty alcohols.

In another embodiment composite fatty acids such as from coconut oil,palm oil, tallow and jojoba oil may be used.

In one or more embodiments, the waxes can be solid substances and in oneor more embodiments they may be liquid. In other embodiments acombination of liquid and solid molecules is used.

In an embodiment a saturated fatty acid such as isostearic acid orstearic acid, is preferable due to the stability and the easyoverlapping application. These fatty acids may be used alone or in anymixture thereof. For example, for higher concentrations isostearic acidcan be used alone or in combination with stearic acid. Indeed, skinfeeling can be improved when two or more fatty acids such as stearicacid and isostearic acid are used in combination. The same reasoning isapplicable with appropriate changes to fatty alcohols.

In one or more embodiments, the waxes can act as a solvent.

In one or more embodiments, the waxes can act as an emollient.

In one or more embodiments, the waxes can act as a penetration enhancer.

In one or more embodiments, where they are branched or unsaturated theycan provide some substantially organized chaos by virtue of their nonlinear shape enabling both shakability and flowability of the waxformulation and potentially enhanced skin penetration.

Nature moves or tends towards chaos although passing through certainstable states on the way. In a foamable formulation comprising an oilphase and a water phase it is desirable to form a stable emulsion by useof surfactants. Where the surfactant comprises for example, fatty acidor alcohol chains it can form a reasonably tightly packed layer wherethe said fatty acid or alcohol chains are straight chain and saturated.Relatively speaking such a layer can be considered organised. Ifunsaturated chains or branched are introduced or used then the moleculesare not straight and the backbone can have a mild “v” shape like inoleic acid or in erucic acid or a more pronounced “v” as in linoleicacid or a “u” shape as in arachidonic acid or a half “w” shape as inlinolenic acid or a “t” shape in isostearic acid. Without being bound byany theory by using such non linear molecules in forming a foamablecomposition the surfactant layer or interphase is likely to be lesspacked and more disrupted making the surfactant layer or interphase invery general terms more fluid and fluidizing, which in turn may improvethe flowability of the formulation and or also skin or mucosal membranepenetration. The presence of fatty acids or fatty alcohols in theformulation can interfere with the packing of the surfactant layer orinterphase and depending on the surfactants and fatty acids and oralcohols used can improve or disrupt the packing and intern theoil/water interphase. By substantially organized with reference to asurfactant layer of an oil and water or wax and water emulsion is meanta relatively organised well packed layer holding the oil and water orwax and water phases together. By substantially organized chaos it ismeant to refer to and to describe a surfactant layer or interphase wherecomparatively it is to some extent being disrupted and tending towardssome chaos or increased liquidity and fluidization or being less tightlypacked, due to the selected use of such non linear molecules in thecomposition. The effect of this substantially organised chaos may varyfrom formulation to formulation and may be influenced by surface andinterfacial tensions. In other words whilst there is an overallstructuring effect in the formulation due to the stabiliser and or thefatty acids and or fatty alcohols the effect can be modulated orpartially or temporarily disrupted by introducing a non linear moleculewhich facilitates for example liquidity, fluidization and orpenetration. In addition this phenomenon can have an effect on thesolubility of certain active agents both in the formulation and or inthe interphase.

In one or more embodiments, certain waxes can act as a foam adjuvant.

In one or more embodiments, the fatty alcohol is oleyl alcohol.

Oleyl alcohol occurs as a pale yellow oily liquid and is sometimes usedas an antifoaming agent; solubilizing agent/dissolution enhancer;emollient; emulsifying agent; skin penetrant; and sustained-releaseagent. Oleyl alcohol is mainly used in topical pharmaceuticalformulations and has been used in transdermal delivery formulations. Ithas been utilized in aerosol formulations of insulin and albuterol.Therapeutically, it has been suggested that oleyl alcohol may exhibitantitumor properties via transmembrane permeation. Oleyl alcohol issoluble in ethanol (95%), and ether but practically insoluble in waterand should be stored in a well-closed container in a cool, dry, place.Oleyl alcohol is mainly used in topical pharmaceutical formulations andis generally regarded as a nontoxic and nonirritant material at thelevels employed as an excipient although contact dermatitis due to oleylalcohol has been reported. Oleyl alcohol and propylene glycol aremiscible although they are hydrophobic and hydrophilic and therefore itis predicted that it should be possible to make waterless waxy or waxysubstances foamable compositions and foam. To the extent that isostearicacid and propylene glycol or stearic acid and propylene glycol arelikewise miscible the same will apply to them.

In one or more embodiments, the fatty acid is isostearic acid.

Isostearic acid is a naturally occurring fatty acid, primarilycomprising methyl branched isomers of octadecanoic acid. It main uses inthe cosmetic and pharmaceutical industries are as a binding agent as anemulsifier/surfactant and as a lubricant It is a nearly water-whiteliquid with a very low odor. Isostearic acid is an emollient that canform a lipid film on the skin that is permeable to water vapor, oxygen,and carbon dioxide. Isostearic acid is recommended for use inmoisturizing cosmetics and is similar to waxes secreted by birds forfeather maintenance. Isostearic acid, provides a combination of theproperties (from the C₁₈ chain length) including retaining the stabilityof stearic acid the with the liquidity, solubility and physicalproperties conferred by oleic acid but without the disadvantage of theunsaturation.

In one or more embodiments, the fatty acid is oleic acid.

Oleic acid is a yellowish to pale brown, oily liquid that has been usedas an emulsifying agent in topical pharmaceutical formulations. It hasalso been used as a penetration enhancer in transdermal formulations. Itis miscible with ethanol (95%), ether, hexane, and fixed and volatileoils; but practically insoluble in water. On exposure to air, oleic acidgradually absorbs oxygen and darkens in color. At atmospheric pressure,it decomposes when heated at 80-100° C. Oleic acid should be stored in awell-filled, well-closed container, protected from light, in a cool, dryplace. Oleic acid is incompatible with aluminum, calcium, heavy metals,iodine solutions, perchloric acid, and oxidizing agents and also reactswith alkalis to form soaps.

In one or more embodiments, the fatty acid is stearic acid.

Stearic acid (octadecanoic acid) is a straight chain fatty acid and maycontain palmitic acid. Stearic acid is widely used in oral and topicalpharmaceutical formulations and in cosmetics It has been used as anemulsifying agent and solubilizing agent; as a foam adjuvant, alubricant, and binder. Stearic acid has also been suggested as asustained-release drug carrier. When partially neutralized with alkalisor triethanolamine, stearic acid is used in the preparation of creams.It is soluble in ethanol (95%), hexane, and propylene glycol but ispractically insoluble in water. Stearic acid is incompatible with mostmetal hydroxides and may be incompatible with oxidizing agents. Studieshave suggested possible drug incompatibilities, e.g. with naproxen.Nevertheless, it is generally regarded as a nontoxic and nonirritantmaterial, although it is combustible.

In one or more embodiments, isostearic acid and stearic acid are used incombination.

In one or more embodiments, oleyl alcohol and stearic acid are used incombination.

In one or more embodiments, oleyl alcohol and stearic acid are used incombination.

In one or more embodiments, at least any two from the group consistingof caprilic acid. capryl alcohol, capric acid, capric alcohol, palmiticacid, cetyl alcohol, stearic acid, isostearic acid, stearyl alcohol, andoleyl alcohol are used in combination.

In one or more embodiments, a fatty alcohol is used in combination witha fatty acid. In an embodiment the amount of fatty alcohol is in excessof the amount of fatty acid. In an embodiment the ratio of fatty alcoholto fatty acid is about 10:9, about 5:4, about 4:3, about 3:2, about 2:1,about 3:1, about 4:1, about 5:1, about 8:1, about 10:1, about 20:1,about 40:1, about 80:1, or is any ratio between these ratios.

In one or more embodiments, a liquid wax is used in combination with asolid wax. In an embodiment the amount of liquid wax is in excess of theamount of solid wax. In an embodiment the ratio of liquid wax to solidwax is about 5:4, about 4:3, about 3:2, about 2:1, about 3:1, about 4:1,about 5:1, about 10:1, about 20:1, about 40:1, about 80:1, or is anyratio between these ratios. In another embodiment the amount of solidwax is in excess of the amount of liquid wax. In an embodiment the ratioof solid wax to liquid wax is about 5:4, about 4:3, about 3:2, about2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1,about 10:1, or is any ratio between these ratios.

In one or more embodiments, the fatty acid and the fatty alcohol can belinked by a linker. A natural example is found in jojoba oil.

Jojoba oil (pronounced “ho-HO-bah”) is the liquid wax produced in theseed of the Jojoba (Simmondsia chinensis) plant. Jojoba oil is astraight chain wax ester, 36 to 46 carbon atoms in length. Each moleculeconsists of a fatty acid and a fatty alcohol joined by an ester bond.Each molecule has two points of cis-unsaturation, both located at the9th carbon atom from either end of the molecule. Jojoba oil comprisesapproximately 66-71% eicosenoic acid, 14-20% docosenoic acid and 10-13%oleic acid. Refined jojoba oil is colorless and odorless. The meltingpoint of jojoba oil is approximately 10° C. Jojoba oil is relativelyshelf-stable when compared with other vegetable oils. Unlike commonvegetable oils, jojoba oil is chemically very similar to human sebum.Most jojoba oil is used as an ingredient in cosmetics and personal careproducts, especially skin care and hair care. Therapeutically it can aidin the healing process.

Sebum acts to protect and waterproof hair and skin, and keep them frombecoming dry, brittle and cracked. It can also inhibit the growth ofmicroorganisms on skin. It is thought that likewise, formulations withsubstances such as waxes that can mimic sebum for example like jojobaoil, stearic acid, isostearic acid, oleyl alcohol and the like includingcombinations thereof and especially in higher concentrations can provideprotection to the hair and skin.

In one embodiment a foamable composition as described herein includes(a) at least about 10% by weight jojoba oil; (b) a stabilizer componentcomprising a surface-active agent, a polymeric agent or a mixturethereof; (c) water; and (d) a liquefied hydrocarbon gas propellant.

In one embodiment a foamable composition as described herein includes(a) at least about 10% by weight jojoba oil; (b) a stabilizer componentcomprising a surface-active agent, a polymeric agent or a mixturethereof; (c) water; and (d) a liquefied hydrocarbon gas propellant, inwhich the ratio of the component, the stabilizer and water to the gaspropellant is about 100:3 by weight to about 100:35 by weight;

wherein the composition is substantially free from crystals and issubstantially flowable; andin which, when the stabilizer component comprises a polymeric agent, thepolymeric agent is present in the vehicle composition at a concentrationof about 0.01% to about 5% by weight and includes a bioadhesive agent, agelling agent, a film forming agent and a phase change agent; andwherein, upon release from a pressurized container, the foam produced isbreakable.

In another embodiment the jojoba foamable composition further includes asolid wax. In an alternative embodiment the jojoba foamable compositionincludes another liquid wax. In a further embodiment the jojoba foamablecomposition includes another liquid wax and a solid wax

In further embodiment the jojoba composition includes a liquid wax,wherein the concentration of the liquid wax and the jojoba oil togetherin the composition is at least about 20% by weight. In one or morefurther embodiments the concentration is at least about 25% by weight;30% by weight; 35% by weight; or 40% by weight.

In a still further embodiment the jojoba composition comprises a liquidwax and a solid wax wherein the concentration of the liquid wax, thesolid wax and the jojoba oil together in the composition is at leastabout 20% by weight. In one or more further embodiments theconcentration is at least about 25% by weight; 30% by weight; 35% byweight; or 40% by weight.

In one or more embodiments, the fatty acid or alcohol is a biologicallyactive. For example, benhenyl alcohol has some antiviral properties. Inan embodiment, biologically active fatty acid or alcohol possesseskeratolytic activities.

In an embodiment, the waxy substance is incorporated in the foamablecomposition in a safe and effective amount. The term “safe andeffective” means an amount of an active agent that exerts a therapeuticeffect on a specific disorder, without causing adverse effects that mayprohibit the use of said active agent in the treatment of said disorder.

Although the presence of fatty acids and or fatty alcohol in theformulations may be high the formulations are substantially nonirritating for one or more of the following reasons. By providing andapplying the wax formulations in a low density foam preparation onlyrelatively small amounts may be needed to cover a target surface whencompared to a cream. Low levels of surfactants preferably non ionic areused. Non or low irritant waxes are selected that are safe andeffective. By providing formulations in which the waxes and any activeingredients are dissolved the formulations are substantially free fromcrystals or particles which can irritate the skin.

In one or more embodiments, the wax, waxy substance, counterpart orderivative thereof contributes to the foam structure.

In one or more embodiments, the fatty acid is present in the compositionin an ionized state.

In one or more embodiments, the ratio of wax to water is about 1:50;about 1:25, about 1:10; about 1:9; about 1:5; about 1:3; about 2:5;about 1:2; about; 3:5; about 2:3; about 1:1; about 3:2; about 5:3 about2:1 about 3:1; about 4:1; about 5:1; about 9:1; or about 10:1.

The sensory properties of foams containing a waxy substance arefavorable.

Foam Adjuvant

Optionally, the foamable vehicle further includes a foam adjuvantselected from the group consisting of a fatty alcohol having 15 or morecarbons in their carbon chain; a fatty acid having 16 or more carbons intheir carbon chain; fatty alcohols, derived from beeswax and including amixture of alcohols, a majority of which has at least 20 carbon atoms intheir carbon chain; a fatty alcohol having at least one double bond; afatty acid having at least one double bond; a branched fatty alcohol; abranched fatty acid and a fatty acid substituted with a hydroxyl groupand mixtures thereof and wherein the foam adjuvant is solid or waxy atroom temperature or if a mixture at least one of the mixture is solid orwaxy at room temperature.

In one or more embodiments the foam adjuvant is a wax, waxy substance,counterparts or derivative thereof.

Additional Organic Carrier

Optionally, the foamable vehicle further includes at least oneadditional organic carrier selected from the group consisting of ahydrophobic organic carrier, an emollient and mixtures thereof, at aconcentration of about 2% to about 50% by weight. The hydrophobicsolvent and/or the emollient can be selected from the group consistingof mineral oil, triglycerides, capric/caprylic triglyceride, alkylesters of fatty acids such as isopropyl palmitate, isopropylisostearate, octyl palmitate, cetyl lactate, cetyl ricinoleate,tocopheryl acetate, acetylated lanolin alcohol, cetyl acetate, phenyltrimethicone, glyceryl oleate, tocopheryl linoleate, wheat germglycerides, arachidyl propionate, myristyl lactate, decyl oleate,ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate,neopentylglycol dicaprylate/dicaprate, isononyl isononanoate,isotridecyl isononanoate, myristyl myristate, triisocetyl citrate, octyldodecanol, maleated soybean oil, unsaturated or polyunsaturated oils,such as olive oil, corn oil, soybean oil, canola oil, cottonseed oil,coconut oil, sesame oil, sunflower oil, borage seed oil, syzigiumaromaticum oil, hempseed oil, herring oil, cod-liver oil, salmon oil,flaxseed oil, wheat germ oil, evening primrose oils; essential oils; andsilicone oils, such as dimethicone, cyclomethicone, polyalkyl siloxane,polyaryl siloxane, polyalkylaryl siloxane, a polyether siloxanecopolymer and a poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer.

In an embodiment, the organic carrier is a polypropylene glycol alkylether (PPG alkyl ether). PPG alkyl ethers are liquid, water-insolublepropoxylated fatty alcohols, having the molecular formula ofRO(CH₂CHOCH₃)_(n); wherein “R” is a straight-chained or branched C₄ toC₂₂ alkyl group; and “n” is in the range between 4 and about 50. Theyare organic liquids that function as skin-conditioning agent inpharmaceutical and cosmetic formulations. Non-limiting exemplary PPGalkyl ethers include PPG stearyl ethers and PPG Butyl Ether. PreferredPPG alky ethers according to the present invention include PPG-15Stearyl Ether, PPG-2 Butyl Ether, PPG-9-13 Butyl Ether and PPG-40 ButylEther.

In an embodiment, the organic carrier is a paraffin, glycerin or apetrolatum, which is also termed “white petrolatum” and “Vaseline”.Preferably, one or more of paraffin, glycerin or petroleum used atbetween about 1% to about 5%.

Polymeric Agent

In some embodiments, the composition contains a polymeric agent selectedfrom the group consisting of a bioadhesive agent, a gelling agent, afilm forming agent and a phase change agent. A polymeric agent enhancesthe creation of foam having fine bubble structure, which does notreadily collapse upon release from the pressurized aerosol can. Thepolymeric agent serves to stabilize the foam composition and to controldrug residence in the target organ.

Exemplary polymeric agents include, in a non-limiting manner,naturally-occurring polymeric materials, such as locust bean gum, sodiumalginate, sodium caseinate, egg albumin, gelatin agar, carrageenin gum,sodium alginate, xanthan gum, quince seed extract, tragacanth gum, guargum, cationic guars, hydroxypropyl guar gum, starch, amine-bearingpolymers such as chitosan; acidic polymers obtainable from naturalsources, such as alginic acid and hyaluronic acid; chemically modifiedstarches and the like, carboxyvinyl polymers, polyvinylpyrrolidone,polyvinyl alcohol, polyacrylic acid polymers, polymethacrylic acidpolymers, polyvinyl acetate polymers, polyvinyl chloride polymers,polyvinylidene chloride polymers and the like.

Additional exemplary polymeric agents include semi-synthetic polymericmaterials such as cellulose ethers, such as methylcellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxy propylmethyl cellulose, methylhydroxyethylcellulose,methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose,carboxymethyl cellulose, carboxymethylcellulosecarboxymethylhydroxyethylcellulose, and cationic celluloses, carbomer(homopolymer of acrylic acid is crosslinked with an allyl etherpentaerythritol, an allyl ether of sucrose, or an allyl ether ofpropylene, such as Carbopol® 934, Carbopol® 940, Carbopol® 941,Carbopol® 980 and Carbopol® 981, pemulen, klucel, and aluminum starchoctenylsuccinate (ASOS) or other derivatized polymers. Polyethyleneglycol, having molecular weight of 1000 or more (e.g., PEG 1,000, PEG4,000, PEG 6,000 and PEG 10,000) also have gelling capacity and whilethey are considered herein as “secondary polar solvents”, as detailedherein, they are also considered polymeric agents.

In one or more embodiments the polymeric agents have emulsifyingproperties. In certain preferred embodiments the polymeric agent is aderivatized hydrophilic polymer with hydrophobic alkyl moieties Othertypes that may also a similar stabilizing effect are silicone copolymersand derivatized starch aluminum starch octenyl succinate (ASOS).

In an embodiment the polymeric agent is a polymeric surfactantPoloxamer. Poloxamer is a synthetic block copolymer of ethylene oxideand propylene, having the general formula of:

For the generic term “Poloxamer”, these copolymers are commonly namedwith the letter “P” (for Poloxamer) followed by three digits, the firsttwo digits×100 give the approximate molecular mass of thepolyoxypropylene core, and the last digit×10 gives the percentagepolyoxyethylene content. For example, P407 is a Poloxamer with apolyoxypropylene molecular mass of 4,000 g/mol and a 70% polyoxyethylenecontent. A non limiting list is 124, 181, 182, 183, 184, 185, 188, 212,215, 217, 231, 234, 235, 237, 238, 331, 333, 334, 3338, 335, 401, 402,403 and 407.

Mixtures of the above polymeric agents are contemplated.

The concentration of the polymeric agent should be selected so that thecomposition, after filling into aerosol canisters, is flowable, and canbe shaken in the canister. In one or more embodiments, the concentrationof the polymeric agent is selected such that the viscosity of thecomposition, prior to filling of the composition into aerosol canisters,is about or less than 12,000 CPs, and more preferably, less than 10,000CPs. Nevertheless where waxy substances are used in the compositionespecially in higher concentrations the viscosity may substantiallyexceed these figures.

In one or more embodiments the polymeric agent is a water misciblepolymeric agent.

In one or more embodiments the polymeric agent is selected from at leastone of the group consisting of pemulen, carboxymethyl cellulose (CMC),carbomer, klucel, hydroxyl propyl methyl cellulose and xantham gum.

Surface Active Agent

In some embodiments, the composition contains a surface-active agent.Surface-active agents (also termed “surfactants”) include any agentlinking oil and water in the composition, in the form of emulsion. Asurfactant's hydrophilic/lipophilic balance (HLB) describes theemulsifier's affinity toward water or oil. HLB is defined for non-ionicsurfactants. The HLB scale ranges from 1 (totally lipophilic) to 20(totally hydrophilic), with 10 representing an equal balance of bothcharacteristics. Lipophilic emulsifiers form water-in-oil (w/o)emulsions; hydrophilic surfactants form oil-in-water (o/w) emulsions.The HLB of a blend of two emulsifiers equals the weight fraction ofemulsifier A times its HLB value plus the weight fraction of emulsifierB times its HLB value (weighted average). In many cases a singlesurfactant may suffice. In other cases a combination of two or moresurfactants is desired. Reference to a surfactant in the specificationcan also apply to a combination of surfactants or a surfactant system.As will be appreciated by a person skilled in the art which surfactantor surfactant system is more appropriate is related to the vehicle andintended purpose. In general terms a combination of surfactants isusually preferable where the vehicle is an emulsion. In an emulsionenvironment a combination of surfactants can be significant in producingbreakable forms of good quality. It has been further discovered that thegenerally thought considerations for HLB values for selecting asurfactant or surfactant combination are not always binding foremulsions and that good quality foams can be produced with a surfactantor surfactant combination both where the HLB values are in or towardsthe lipophilic side of the scale and where the HLB values are in ortowards the hydrophilic side of the scale. Surfactants also play a rolein foam formation where the foamable formulation is a single phasecomposition.

According to one or more embodiments the composition contains a singlesurface active agent having an HLB value between about 2 and 9, or morethan one surface active agent and the weighted average of their HLBvalues is between about 2 and about 9. Lower HLB values may in certainembodiments be more applicable to water in oil emulsions.

According to one or more embodiments the composition contains a singlesurface active agent having an HLB value between about 7 and 14, or morethan one surface active agent and the weighted average of their HLBvalues is between about 7 and about 14. Mid range HLB values may incertain embodiments be more suitable for oil in water emulsions.

According to one or more other embodiments the composition contains asingle surface active agent having an HLB value between about 9 andabout 19, or more than one surface active agent and the weighted averageof their HLB values is between about 9 and about 19.

Preferably, the composition contains a non-ionic surfactant. Nonlimitingexamples of possible non-ionic surfactants include a polysorbate,polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20)sorbitan monooleate, a polyoxyethylene fatty acid ester, Myrj 45, Myrj49, Myrj 52 and Myrj 59; a polyoxyethylene alkyl ether, polyoxyethylenecetyl ether, polyoxyethylene palmityl ether, polyethylene oxidehexadecyl ether, polyethylene glycol cetyl ether, steareths such assteareth 2, brij 21, brij 721, brij 38, brij 52, brij 56 and brij W1, asucrose ester, a partial ester of sorbitol and its anhydrides, sorbitanmonolaurate, sorbitan monolaurate, a monoglyceride, a diglyceride,isoceteth-20 and mono-, di- and tri-esters of sucrose with fatty acids.In certain embodiments, suitable sucrose esters include those havinghigh monoester content, which have higher HLB values. In an embodimentthe alkyl or fatty acid polyoxyalkylene ether or ester respectively isnot less than C14.

In certain embodiments with wax as emollient, surfactants are selectedwhich can provide a close packed surfactant layer separating the oil andwater phases. To achieve such objectives combinations of at least twosurfactants are selected. Preferably, they should be complex emulgatorsand more preferably they should both be of a similar molecular type. Forexample, a pair of ethers, like steareth 2 and steareth 21, or a pair ofesters, such as, PEG-40 stearate and polysorbate 80 may be used. InCertain circumstances POE esters cannot be used and a combination ofsorbitan laurate and sorbitan stearate or a combination of sucrosestearic acid ester mixtures and sodium laurate may be used. All thesecombinations due to their versatility and strength may also be usedsatisfactorily and effectively with wax formulations, although theamounts and proportion may be varied according to the formulation andits objectives as will be appreciated by a man of the art.

It has been discovered also that by using a derivatized hydrophilicpolymer with hydrophobic alkyl moieties as a polymeric emulsifier suchas pemulen it is possible to stabilize the emulsion better about or atthe region of phase reversal tension. Other types of derivatizedpolymers like silicone copolymers, derivatized starch [Aluminum StarchOctenylsuccinate (ASOS)]/[DRY-FLO AF Starch], and derivatized dexrin mayalso a similar stabilizing effect.

A series of dextrin derivative surfactants prepared by the reaction ofthe propylene glycol polyglucosides with a hydrophobicoxirane-containing material of the glycidyl ether are highlybiodegradable. [Hong-Rong Wang and Keng-Ming Chen, Colloids and SurfacesA: Physicochemical and Engineering Aspects Volume 281, Issues 1-3, 15Jun. 2006, Pages 190-193].

Non-limiting examples of non-ionic surfactants that have HLB of about 7to about 12 include steareth 2 (HLB˜4.9); glyceryl monostearate/PEG 100stearate (Av HLB˜11.2); stearate Laureth 4 (HLB˜9.7) and cetomacrogolether (e.g., polyethylene glycol 1000 monocetyl ether).

Non-limiting examples of preferred surfactants, which have a HLB of 4-19are set out in the Table below:

Surfactant HLB steareth 2 ~4.9 glyceryl monostearate/PEG 100 stearate Av~11.2 Glyceryl Stearate ~4 Steareth-21 ~15.5 peg 40 stearate ~16.9polysorbate 80 ~15 sorbitan stearate ~4.7 laureth 4 ~9.7 Sorbitanmonooleate (span 80) ~4.3 ceteareth 20 ~15.7 steareth 20 ~15.3 ceteth 20~15.7 Macrogol Cetostearyl Ether ~15.7 ceteth 2 (Lipocol C-2) ~5.3PEG-30 Dipolyhydroxystearate ~5.5 sucrose distearate (Sisterna SP30) ~6polyoxyethylene (100) stearate ~18.8

More exemplary stabilizing surfactants which may be suitable for use inthe present invention are found below.

PEG-Fatty Acid Monoester Surfactants

Chemical name Product example name HLB PEG-30 stearate Myrj 51 >10PEG-40 laurate Crodet L40 (Croda) 17.9 PEG-40 oleate Crodet O40 (Croda)17.4 PEG-45 stearate Nikkol MYS-45 (Nikko) 18 PEG-50 stearate Myrj53 >10 PEG-100 stearate Myrj 59, Arlacel 165 (ICI) 19

PEG-Fatty Acid Diester Surfactants:

Chemical name Product example name HLB PEG-4 dilaurate Mapeg .RTM. 200DL (PPG), 7 Kessco .RTM.PEG 200 DL (Stepan), LIPOPEG 2-DL (Lipo Chem.)PEG-4 distearate Kessco .RTM. 200 DS 5 (Stepan.sub) PEG-32 dioleateKessco .RTM. PEG 1540 DO (Stepan) 15 PEG-400 dioleate Cithrol 4DO series(Croda) >10 PEG-400 disterate Cithrol 4DS series (Croda) >10 PEG-20glyceryl oleate Tagat .RTM. O (Goldschmidt) >10

Transesterification Products of Oils and Alcohols

Chemical name Product example name HLB PEG-30 castor oil Emalex C-30(Nihon Emulsion) 11 PEG-40 hydrogenated Cremophor RH 40 (BASF), 13castor oil Croduret (Croda), Emulgin HRE 40 (Henkel)

Polyglycerized Fatty Acids, Such as:

Chemical name Product example name LB Polyglyceryl-6 Caprol .RTM. 6G20(ABITEC); 8.5 dioleate PGO-62 (Calgene), PLUROL OLEIQUE CC 497(Gattefosse)Hodag

PEG-Sorbitan Fatty Acid Esters

Chemical name Product example name HLB PEG-20 sorbitan Tween-20(Atlas/ICI), Crillet 1 17 monolaurate (Croda), DACOL MLS 20 (Condea)PEG-20 sorbitan Tween 40 (Atlas/ICI), Crillet 2 16 Monopalmitate (Croda)PEG-20 sorbitan Tween-60 (Atlas/ICI), Crillet 3 15 monostearate (Croda)PEG-20 sorbitan Tween-80 (Atlas/ICI), Crillet 4 15 monooleate (Croda)

Polyethylene Glycol Alkyl Ethers

Chemical name Product example name HLB PEG-2 oleyl ether oleth-2 Brij92/93 (Atlas/ICI) 4.9 PEG-3 oleyl ether oleth-3 Volpo 3 (Croda) <10PEG-5 oleyl ether oleth-5 Volpo 5 (Croda) <10 PEG-10 oleyl etheroleth-10 Volpo 10 (Croda), Brij 12 96/97 (Atlas/ICI) PEG-20 oleyl etheroleth-20 Volpo 20 (Croda), Brij 15 98/99 (Atlas/ICI) PEG-4 lauryl etherlaureth-4Brij 30 (Atlas/ICI) 9.7 PEG-23 lauryl ether laureth-23Brij 35(Atlas/ICI) 17 PEG-10 stearyl ether Brij 76 (ICI) 12 PEG-2 cetyl etherBrij 52 (ICI) 5.3

Sugar Ester Surfactants

Chemical name Product example name HLB Sucrose distearate Sisterna SP50,Surfope 1811 11

Sorbitan Fatty Acid Ester Surfactants

Chemical name Product example name HLB Sorbitan monolaurate Span-20(Atlas/ICI), Crill 1 8.6 (Croda), Arlacel 20 (ICI) Sorbitanmonopalmitate Span-40 (Atlas/ICI), Crill 2 6.7 (Croda), Nikkol SP-10(Nikko) Sorbitan monooleate Span-80 (Atlas/ICI), Crill 4 4.3 (Croda),Crill 50 (Croda) Sorbitan monostearate Span-60 (Atlas/ICI), Crill 3 4.7(Croda), Nikkol SS-10 (Nikko)

In one or more embodiments the surface active agent is a combination oftwo or more surface active agents that can be more effective than asingle surfactant and provides a more stable emulsion or improved foamquality than a single surfactant. For example and by way of non-limitingexplanation it has been found that by choosing say two surfactants, onehydrophobic and the other hydrophilic the combination can produce a morestable emulsion than a single surfactant. Preferably, the complexemulgator comprises a combination of surfactants wherein there is adifference of about 4 or more units between the HLB values of the twosurfactants or there is a significant difference in the chemical natureor structure of the two or more surfactants. Without being bound by anytheory by appropriate selection of a liquid wax and or a solid wax touse with a surfactant pair (and vice versa) the packing of thesurfactant layer or interphase can be effected and may result in a lesspacked and more disrupted layer or interphase by choosing a branched andor unsaturated wax or a more packed less disrupted layer or interphaseby selecting straight chain saturated waxes. Nevertheless, anappropriate single surfactant with a liquid wax or a solid wax ormixtures thereof can also have a similar effect on the surfactant layeror interphase.

Specific non limiting examples of surfactant systems are, combinationsof polyoxyethylene alkyl ethers, such as Brij 59/Brij10; Brij 52/Brij10; Steareth 2/Steareth 20; Steareth 2/Steareth 21 (Brij 72/Brij 721);combinations of polyoxyethylene stearates such as Myrj 52/Myrj 59;combinations of sucrose esters, such as Surphope 1816/Surphope 1807;combinations of sorbitan esters, such as Span 20/Span 80; Span 20/Span60; combinations of sucrose esters and sorbitan esters, such as Surphope1811 and Span 60; combinations of liquid polysorbate detergents and PEGcompounds, such as Tween 80/PEG-40 stearate; methyl glucasosequistearate; polymeric emulsifiers, such as Permulen (TRI or TR2);liquid crystal systems, such as Arlatone (2121), Stepan (Mild RM1),Nikomulese (41) and Montanov (68) and the like.

In certain embodiments the surfactant is preferably one or more of thefollowing: a combination of steareth-2 and steareth-21 on their own orin combination with glyceryl monostearate (GMS); in certain otherembodiments the surfactant is a combination of polysorbate 80 and PEG-40stearate. In certain other embodiments the surfactant is a combinationof glyceryl monostearate/PEG 100 stearate. In certain other embodimentsthe surfactant is a combination of two or more of stearate 21, PEG 40stearate, and polysorbate 80. In certain other embodiments thesurfactant is a combination of two or more of laureth 4, span80, andpolysorbate 80. In certain other embodiments the surfactant is acombination of two or more of GMS and ceteareth. In certain otherembodiments the surfactant is a combination of two or more of steareth21, ceteareth 20, ceteth 2 and laureth 4 In certain other embodimentsthe surfactant is a combination of ceteareth 20 and polysorbate 40stearate. In certain other embodiments the surfactant is a combinationof span 60 and GMS. In certain other embodiments the surfactant is acombination of two or all of PEG 40 stearate, sorbitan stearate andpolysorbate 60

In certain other embodiments the surfactant is one or more of sucrosestearic acid esters, sorbitan laureth, and sorbitan stearate.

Without being bound by any particular theory or mode of operation, it isbelieved that the use of non-ionic surfactants with significanthydrophobic and hydrophilic components, increase the emulsifier or foamstabilization characteristics of the composition. Similarly, withoutbeing bound by any particular theory or mode of operation, usingcombinations of surfactants with high and low HLB's to provide arelatively close packed surfactant layer may strengthen the emulsion.

In one or more embodiments the stability of the composition can beimproved when a combination of at least one non-ionic surfactant havingHLB of less than 9 and at least one non-ionic surfactant having HLB ofequal or more than 9 is employed. The ratio between the at least onenon-ionic surfactant having HLB of less than 9 and the at least onenon-ionic surfactant having HLB of equal or more than 9, is between 1:8and 8:1, or at a ratio of 4:1 to 1:4. The resultant HLB of such a blendof at least two emulsifiers is preferably between about 9 and about 14.

Thus, in an exemplary embodiment, a combination of at least onenon-ionic surfactant having HLB of less than 9 and at least onenon-ionic surfactant having HLB of equal or more than 9 is employed, ata ratio of between 1:8 and 8:1, or at a ratio of 4:1 to 1:4, wherein theHLB of the combination of emulsifiers is preferably between about 5 andabout 18.

In certain cases, the surface active agent is selected from the group ofcationic, zwitterionic, amphoteric and ampholytic surfactants, such assodium methyl cocoyl taurate, sodium methyl oleoyl taurate, sodiumlauryl sulfate, triethanolamine lauryl sulfate and betaines.

Many amphiphilic molecules can show lyotropic liquid-crystalline phasesequences depending on the volume balances between the hydrophilic partand hydrophobic part. These structures are formed through themicro-phase segregation of two incompatible components on a nanometerscale. Soap is an everyday example of a lyotropic liquid crystal.Certain types of surfactants tend to form lyotropic liquid crystals inemulsions interface (oil-in-water) and exert a stabilizing effect

In one or more embodiments the surfactant is a surfactant or surfactantcombination is capable of or which tends to form liquid crystals.Surfactants which tend to form liquid crystals may improve the qualityof foams. Non limiting examples of surfactants with postulated tendencyto form interfacial liquid crystals are: phospholipids, alkylglucosides, sucrose esters, sorbitan esters.

In one or more embodiments the at least one surface active agent isliquid.

In one or more embodiments the liquid surfactant is a polysorbate,preferably polysorbate 80 or 60.

In one or more embodiments the at least one surface active agent issolid, semi solid or waxy.

In one or more embodiments the surfactant can be, a surfactant systemcomprising of a surfactant and a co surfactant, a waxy emulsifier, aliquid crystal emulsifier, an emulsifier which is solid or semi solid atroom temperature and pressure, or combinations of two or more agents inan appropriate proportion as will be appreciated a person skilled in theart. Where a solid or semi solid emulsifier combination is used it canalso comprise a solid or semi solid emulsifier and a liquid emulsifier.

In one or more embodiments, the surface-active agent includes at leastone non-ionic surfactant. Ionic surfactants are known to be irritants.Therefore, non-ionic surfactants are preferred in applications includingsensitive tissue such as found in most mucosal tissues, especially whenthey are infected or inflamed. Non-ionic surfactants alone can provideformulations and foams of good or excellent quality in the carriers andcompositions.

Thus, in some embodiments, the composition contains a non-ionicsurfactant. In other embodiments the composition includes a mixture ofnon-ionic surfactants as the sole surface active agent. Yet, inadditional embodiments, the foamable composition includes a mixture ofat least one non-ionic surfactant and at least one ionic surfactant in aratio in the range of about 100:1 to 6:1. In one or more embodiments,the non-ionic to ionic surfactant ratio is greater than about 6:1, orgreater than about 8:1; or greater than about 14:1, or greater thanabout 16:1, or greater than about 20:1. In further embodiments, surfaceactive agent comprises a combination of a non-ionic surfactant and anionic surfactant, at a ratio of between 1:1 and 20:1.

In one or more embodiments, a combination of a non-ionic surfactant andan ionic surfactant (such as sodium lauryl sulphate andcocamidopropylbetaine) is employed, at a ratio of between 1:1 and 20:1,or at a ratio of 4:1 to 10:1; for example, about 1:1, about 4:1, about8:1, about 12:1, about 16:1 and about 20:1 or at a ratio of 4:1 to 10:1,for example, about 4:1, about 6:1, about 8:1 and about 10:1.

In selecting a suitable surfactant or combination thereof it should beborne in mind that the upper amount of surfactant that may be used maybe limited by the shakability of the composition. If the surfactant isnon liquid, it can make the formulation to viscous or solid. This can beparticularly significant if the formulation has high molecular weight,e.g., a high molecular weight PEG or polymeric agents or petroleum or ifthe surfactants are large. Solvents and polymeric agents which have highmolecular weight and are very viscous or solid or waxy (e.g., Peg 1500,2000, etc. or petrolatum) can exacerbate the effect of a waxy or solidsurfactant on shakability or flowability. In general terms, as theamount of non-liquid surfactant is increased the shakability of theformulation reduces until a limitation point is reached where theformulation becomes non shakable and unsuitable. Thus in one embodiment,an effective amount of surfactant may be used provided the formulationremains shakable. In other certain exceptional embodiments the upperlimit may be determined by flowability such as in circumstances wherethe composition is marginally or apparently non-shakable. Theformulation is sufficiently flowable to be able to flow through anactuator valve and be released and still expand to form a good qualityfoam.

In certain embodiments the amount of surfactant or combination ofsurfactants may be between about 0.05% to less than about 20%; betweenabout 0.05% to about 15%. or between about 0.05% to about 10%. Althoughthese higher amounts of surfactants may be used nevertheless the amountof surfactants should be reduced or kept low to avoid potentialirritation; depletion of fatty substances from the skin; and dry skinfrom repeated use of the formulations. Thus in some embodiments theconcentration of surface active agent is lower, e.g., between about 0.2%and about 8%. In a further embodiment the concentration of surfaceactive agent is between about 1% and about 5%. By selecting hydrophobicwaxes which can also function as a foam adjuvant in the formulation oras a co surfactant giving support to the surfactant in stabilizing theemulsion and or in producing better foam it is possible to use a smalleramount of surfactant. In a preferred embodiment the hydrophobic waxesare a mixture of a liquid and a solid hydrophobic wax at least one ofwhich can function as a foam adjuvant. In a more preferred embodimentthe formulation comprises a liquid and a solid wax both of which canalso function as a foam adjuvant.

High levels of surfactants which can form a mesomorphic phase should beavoided. Thus, in an embodiment the amount of surfactant or combinationof surfactants is less than that needed to form a mesomorphic phase.

In some embodiments, it is desirable that the surface active agent doesnot contain a polyoxyethylene (POE) moiety, such as polysorbatesurfactants, POE fatty acid esters, and POE alkyl ethers, because theactive agent is incompatible with such surface active agents. Forexample, the active agent pimecrolimus is not stable the presence of POEmoieties, yet benefits greatly from the use of dicarboxylic esters aspenetration enhancers. In such cases, alternative surface active agentsare employed. In an exemplary manner, POE—surfactants includenon-ethoxylated sorbitan esters, such as sorbitan monopalmitate,sorbitan monostearate, sorbitan tristearate, sorbitan monooleate,sorbitan trioleate, sorbitan monolaurate and sorbitan sesquioleate;glycerol fatty acid esters, such as glycerol monostearate and glycerolmonooleate; mono-, di- and tri-esters of sucrose with fatty acids(sucrose esters), sucrose stearate, sucrose distearate sucrose palmitateand sucrose laurate; and alkyl polyglycosides, such as lauryldiglucoside. In an embodiment the surfactant is not a polyoxyethylenefatty acid ester. In an embodiment the surfactant is not apolyoxyethylene alkyl ether. In an embodiment the surfactant is not apolyoxyethylene lauryl ether.

If the composition as formulated is a substantially non shakablecomposition it is nevertheless possible as an exception in the scope forthe formulation to be flowable to a sufficient degree to be able to flowthrough an actuator valve and be released and still expand to form agood quality foam. This surprising and unusual exception may be due oneor more of a number of factors such as the high viscosity, the softness,the lack of crystals, the pseudoplastic or semi pseudo plastic nature ofthe composition and the dissolution of the propellant into thecomposition.

In one or more embodiments, the surface-active agent includes mono-, di-and tri-esters of sucrose with fatty acids (sucrose esters), preparedfrom sucrose and esters of fatty acids or by extraction fromsucro-glycerides. Suitable sucrose esters include those having highmonoester content, which have higher HLB values.

Phase Inversion and Tension

Phase inversion is a factor in the preparation and stabilization ofemulsions and can be both an aid and a detriment. Phase inversioninvolves the change of emulsion type from o/w to w/o or vice versa.Prior to phase inversion occurring there is a tension in the emulsionwhich if destabilized or driven will lead to phase inversion and ifcontrolled or ameliorated or dissipated will result in a more stableemulsion. The occurrence of phase inversion during preparation can be asign of instability. If controlled, it can result in a finer product butif due to other factors after the emulsion was prepared it can causeproblems. Inversion can occur by for example adding calcium chloride toan o/w emulsion stabilized with sodium stearate to form calciumstearate. Inversion can also occur as the product of changes to thephase-volume ratio. For example if a small amount of water is added tosurfactant mixed with oil and agitated a w/o emulsion is formed. As theamount of water added is gradually increased a point will be reachedwhere the water and emulsifier envelop the oil as small droplets to forman o/w emulsion. The amount of each ingredient including the surfactantswill have their part to play in the phenomenon.

Substantially Alcohol-Free

According to one or more embodiments, the foamable composition issubstantially alcohol-free, i.e., free of short chain alcohols. Shortchain alcohols, having up to 5 carbon atoms in their carbon chainskeleton and one hydroxyl group, such as ethanol, propanol, isopropanol,butaneol, iso-butaneol, t-butaneol and pentanol, are considered lessdesirable solvents or polar solvents due to their skin-irritatingeffect. Thus, the composition is substantially alcohol-free and includesless than about 5% final concentration of lower alcohols, preferablyless than about 2%, more preferably less than about 1%.

Substantially Non Aqueous

In certain cases, the active agent degrades in the presence of water,and therefore, in such cases the present of water in the composition isnot desirable. Thus, in certain preferred embodiments, the compositionis substantially non-aqueous. The term “substantially non-aqueous” or“substantially waterless” is intended to indicate that the compositionhas a water content below about 25%.

Shakability

‘Shakability’ means that the composition contains some or sufficientflow to allow the composition to be mixed or remixed on shaking. Thatis, it has fluid or semi fluid properties. In some very limited cases itmay exceptionally be possible to have a foamable composition which isflowable but not apparently shakable.

Breakability

A breakable foam is one that is thermally stable, yet breaks under sheerforce.

The breakable foam is not “quick breaking”, i.e., it does not readilycollapse upon exposure to body temperature environment. Sheer-forcebreakability of the foam is clearly advantageous over thermally inducedbreakability, since it allows comfortable application and well directedadministration to the target area.

Modulating Agent

The term modulating agent is used to describe an agent which can improvethe stability of or stabilize a foamable carrier or composition and oran active agent by modulating the effect of a substance or residuepresent in the carrier or composition.

In one or more embodiments the modulating agent is used in a water inoil or oil in water emulsion

In certain embodiments the substance or residue may for example beacidic or basic and potentially alter pH in an emulsion environment orit may be one or more metal ions which may act as a potential catalystin an emulsion environment.

In one or more embodiments the modulating agent is used to describe anagent which can affect pH in an aqueous solution. The agent can be anyof the known buffering systems used in pharmaceutical or cosmeticformulations as would be appreciated by a man of the art. It can also bean organic acid, a carboxylic acid, a fatty acid an amino acid, anaromatic acid, an alpha or beta hydroxyl acid an organic base or anitrogen containing compound.

In one or more further embodiments the modulating agent is used todescribe an agent, which is a chelating or sequestering or complexingagent that is sufficiently soluble or functional in the solvent toenable it to “mop up” or “lock” metal ions.

In an embodiment modulating agent is used to describe an agent which caneffect pH in an aqueous solution the term modulating agent moreparticularly means an acid or base or buffer system or combinationsthereof, which is introduced into or is present in and acts to modulatethe ionic or polar characteristics and any acidity or basesity balanceof an emulsion carrier, composition, foamable carrier or foamablecomposition or resultant foam.

In one or more embodiments the composition does not contain a modulatingagent. In other embodiments the composition does not contain aneutralizing agent. In further embodiments the composition is notpartially neutralized.

In one or more embodiments the modulating agent comprises an organiccompound.

In one or more embodiments the modulating agent is used to acidify theformulation. In one embodiment it is used to provide an acidic pH, whichis similar to or within the pH range found in healthy skin or in ahealthy body cavity.

In an embodiment the vehicles and foam formulations are furtheracidified with an organic acid, preferably a liquid organic acid, morepreferably an alpha hydroxy acid.

In one or more embodiments the chelating agent is selected from thegroup consisting of ethylenediaminetetraacetic acid (EDTA),diethylenetriaminepentaacetic acid (DTPA),hydroxyethylenediaminetriacetic acid (HEDTA), nitrilotriacetic acid(NTA), O,O′-bis(2-aminoethyl)ethyleneglycol-N,N,N′,N′-tetraacetic acid(EGTA), trans-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid (CyDTA)or a pharmaceutically acceptable salt thereof (normally as a sodiumsalt), more preferably EDTA, HEDTA and their salts; most preferably EDTAand its salts.

In one or more embodiments a non limiting example of the chelating agentis EDTA. Typically, the chelating and sequestering agent is present inthe composition at a level of up to about 5.0%, preferably 1.0 percent,by weight, of the composition.

In one or more embodiments the modulating agent may also be apreservative or an antioxidant or an ionization agent. Any preservative,antioxidant or ionization agents suitable for pharmaceutical or cosmeticapplication may be used. Non limiting examples of antioxidants aretocopherol succinate, propyl galate, butylated hydroxy toluene and butylhydroxy anisol. Ionization agents may be positive or may be negativedepending on the environment and the active agent or composition that isto be protected. Ionization agents may for example act to protect orreduce sensitivity of active agents. Non limiting examples of positiveionization agents are benzyl conium chloride, and cetyl pyridiumchloride. Non limiting examples of negative ionization agents are sodiumlauryl sulphate, sodium lauryl lactylate and phospholipids.

Humectant

A humectant is a substance that helps retain moisture and also preventsrapid evaporation. Non limiting examples are propylene glycol, propyleneglycol derivatives, glycerin, hydrogenated starch hydrosylate,hydrogenated lanolin, lanolin wax, D mannitol, sorbitol, sodium2-pyrrolidone-5-carboxylate, sodium lactate, sodium PCA, solublecollagen, dibutyl phthalate, and gelatin. Other examples may be found inthe Handbook of Pharmaceutical Additives published by Gower.

Moisturizers

A moisturizer, is a substance that helps retain moisture or add backmoisture to the skin. Examples include, without limitation, allantoin,petrolatum, urea, lactic acid, sodium PCV, glycerin, shea butter,caprylic/capric/stearic triglyceride, candelilla wax, propylene glycol,lanolin, hydrogenated oils, squalene, sodium hyaluronate and lysine PCA.Other examples may be found in the Handbook of Pharmaceutical Additivespublished by Gower.

Pharmaceutical compositions may in one or more embodiments usefullycomprise in addition a humectant or a moisturizer or combinationsthereof.

Polar Solvent

Optionally, the foamable vehicle further includes at least one polarsolvent.

A “polar solvent” is an organic solvent, typically soluble in both waterand oil. Certain polar solvents, for example propylene glycol andglycerin, possess the beneficial property of a humectant.

In one or more embodiments, the polar solvent is a humectant.

In one or more embodiments, the polar solvent is a polyol. Polyols areorganic substances that contain at least two hydroxy groups in theirmolecular structure.

In one or more embodiments, the polar solvent contains an diol (acompound that contains two hydroxy groups in its molecular structure),such as propylene glycol (e.g., 1,2-propylene glycol and 1,3-propyleneglycol), butanediol (e.g., 1,4-butaneediol), butanediol (e.g.,1,3-butaneediol and 1,4-butenediol), butynediol, pentanediol (e.g.,1,5-pentanediol), hexanediol (e.g., 1,6-hexanediol), octanediol (e.g.,1,8-octanediol), neopentyl glycol, 2-methyl-1,3-propanediol, diethyleneglycol, triethylene glycol, tetraethylene glycol, dipropylene glycol anddibutylene glycol.

In one or more embodiments, the polar solvent contains a triol (acompound that contains three hydroxy groups in its molecular structure),such as glycerin and 1,2,6-Hexanetriol.

Other non-limiting examples of polar solvents include pyrrolidones,(such as N-methyl-2-pyrrolidone and 1-methyl-2-pyrrolidinone), dimethylisosorbide, 1,2,6-hexapetriol, dimethyl sulfoxide (DMSO), ethylproxitol, dimethylacetamide (DMAc) and alpha hydroxy acids, such aslactic acid and glycolic acid.

According to still other embodiments, the polar solvent is apolyethylene glycol (PEG) or PEG derivative that is liquid at ambienttemperature, including PEG200 (MW (molecular weight) about 190-210 kD),PEG300 (MW about 285-315 kD), PEG400 (MW about 380-420 kD), PEG600 (MWabout 570-630 kD) and higher MW PEGs such as PEG 4000, PEG 6000 and PEG10000 and mixtures thereof.

Polar solvents are known to enhance the penetration of active agent intothe skin and through the skin, and therefore, their inclusion in thecomposition can be desirable, despite their undesirable skin drying andirritation potential. There is at one level a commonality between thedifferent polar solvents and their penetration enhancement properties.Lower molecular weight alcohols can sometimes be more potent as asolvent, for example by extracting lipids from the skin layers moreeffectively, which characteristic can adversely affect the skinstructure and cause dryness and irritation. Therefore the selection oflower molecular weight alcohols is ideally avoided.

Polar solvents, such as detailed below possess high solubilizingcapacity and contribute to the skin penetration of an active agent. Nonlimiting examples include dimethyl isosorbide polyols, such as glycerol(glycerin), propylene glycol, hexylene glycol, diethylene glycol,propylene glycol n-alkanols, terpenes, di-terpenes, tri-terpenes,limonene, terpene-ol, 1-menthol, dioxolane, ethylene glycol, otherglycols, oleyl alcohol, alpha-hydroxy acids, such as lactic acid andglycolic acid, sulfoxides, such as dimethylsulfoxide (DMSO),dimethylformanide, methyl dodecyl sulfoxide, dimethylacetamide, azone(1-dodecylazacycloheptan-2-one), 2-(n-nonyl)-1,3-dioxolane, alkanols,such as dialkylamino acetates, and admixtures thereof. In certainpreferred embodiments, the polar solvent is selected from the groupconsisting of dimethyl isosorbide glycerol (glycerin), propylene glycol,hexylene glycol, terpene-ol, oleyl alcohol, lactic acid and glycolicacid.

Skin Penetration Enhancer

In some embodiments, the compositions described herein include one ormore skin penetration enhancers. A “skin penetration enhancer”, alsotermed herein “penetration enhancer,” is an organic solvent, typicallysoluble in both water and oil. Examples of penetration enhancer includepolyols, such as glycerol (glycerin), propylene glycol, hexylene glycol,diethylene glycol, propylene glycol n-alkanols, terpenes, di-terpenes,tri-terpenes, terpen-ols, limonene, terpene-ol, 1-menthol, dioxolane,ethylene glycol, hexylene glycol, other glycols, sulfoxides, such asdimethylsulfoxide (DMSO), dimethylformanide, methyl dodecyl sulfoxide,dimethylacetamide, dimethylisosorbide, monooleate of ethoxylatedglycerides (with 8 to 10 ethylene oxide units), azone(1-dodecylazacycloheptan-2-one), 2-(n-nonyl)-1,3-dioxolane, esters, suchas isopropyl myristate/palmitate, ethyl acetate, butyl acetate, methylproprionate, capric/caprylic triglycerides, octylmyristate,dodecyl-myristate; myristyl alcohol, lauryl alcohol, lauric acid, lauryllactate ketones; amides, such as acetamide oleates such as triolein;various alkanoic acids such as caprylic acid; lactam compounds, such asazone; alkanols, such as dialkylamino acetates, and admixtures thereof.

According to one or more embodiments, the penetration enhancer is apolyethylene glycol (PEG) or PEG derivative that is liquid at ambienttemperature

Potent Solvent

In one or more embodiments, the foamable composition includes a potentsolvent, in addition to or in place of one of the hydrophobic solvents,polar solvents or emollients of the composition. A potent solvent is asolvent other than mineral oil that solubilizes a specific active agentsubstantially better than a hydrocarbon solvent such as mineral oil orpetrolatum. For example, a potent solvent solubilizes the active agent 5fold better than a hydrocarbon solvent; or even solubilizes the activeagent 10-fold better than a hydrocarbon solvent.

In one or more embodiments, the composition includes at least one activeagent in a therapeutically effective concentration; and at least onepotent solvent in a sufficient amount to substantially solubilize the atleast one active agent in the composition. The term “substantiallysoluble” means that at least 95% of the active agent has beensolubilized, i.e., 5% or less of the active agent is present in a solidstate. In one or more embodiments, the concentration of the at least onepotent solvent is more than about 40% of the at least one solvent of thecomposition; or even more than about 60%.

Non-limiting examples of pairs of active agent and potent solventinclude: Betamethasone valerate: Practically insoluble in mineral oil(<0.01%); soluble more than 1% in glycofurol; Hydrocortisone butyrate:Practically insoluble in mineral oil (<0.01%); soluble more than 1% inglycofurol; Metronidazole: Practically insoluble in mineral oil(<0.01%); soluble more than 1% in dimethyl isosorbide; Ketoconazole:Practically insoluble in mineral oil (<0.01%); soluble more than 1% inglycofurol, propylene glycol and dimethyl isosorbide; Mupirocin:Practically insoluble in mineral oil (<0.01%); soluble more than 1% inglycofurol, hexylene glycol, dimethyl isosorbide, propylene glycol andpolyethylene glycol 400 (PEG 400); Meloxicam, a nonsteroidalanti-inflammatory agent: Practically insoluble in mineral oil (<0.001%);soluble in propylene glycol: 0.3 mg/mL; and in PEG 400: 3.7 mg/mL; andProgesterone: Practically insoluble in mineral oil (<0.001%); soluble inPEG 400: 15.3 mg/mL.

A non-limiting exemplary list of solvents that can be considered aspotent solvents includes polyethylene glycol, propylene glycol, hexyleneglycol, butanediols and isomers thereof, glycerol, benzyl alcohol, DMSO,ethyl oleate, ethyl caprylate, diisopropyl adipate, dimethylacetamide,N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone,isosorbide derivatives, such as dimethyl isosorbide, glycofurol andethoxydiglycol (transcutol) and laurocapram.

The use of a potent solvent in a foam composition provides an improvedmethod of delivering poorly soluble therapeutic agents to a target area.It is known that low drug solubility results in poor bioavailability,leading to decreased effectiveness of treatment. Foam compositions, forwhich the solvent includes a potent solvent, increase the levels of theactive agent in solution and thus, provide high delivery and improvedtherapy.

Potent solvents, as defined herein, are usually liquid. Formulationscomprising potent solvents and active agents are generallydisadvantageous as therapeutics, since their usage involves unwanteddripping and inconvenient method of application; resulting in inadequatedosing. Surprisingly, the foams, which are drip-free, provide a superiorvehicle for such active agents, enabling convenient usage and accurateeffective dosing.

In one or more embodiments the present invention the foamablepharmaceutical composition may additionally include a mixture of two ormore of the solvents selected from the group of hydrophobic solvents,silicone oils, emollients, polar solvents and potent solvents in anappropriate proportion as would be appreciated to a person skilled inthe art.

In one or more embodiments, the PPG alkyl ether may act as a potentsolvent

Additional Components

In an embodiment, a composition includes one or more additionalcomponents. Such additional components include but are not limited toanti perspirants, anti-static agents, buffering agents, bulking agents,chelating agents, cleansers, colorants, conditioners, deodorants,diluents, dyes, emollients, fragrances, hair conditioners, humectants,pearlescent aids, perfuming agents, permeation enhancers, pH-adjustingagents, preservatives, protectants, skin penetration enhancers,softeners, solubilizers, sunscreens, sun blocking agents, sunlesstanning agents, viscosity modifiers and vitamins. As is known to oneskilled in the art, in some instances a specific additional componentmay have more than one activity, function or effect.

Propellants

Suitable propellants include volatile hydrocarbons such as butane,propane, isobutane and fluorocarbon gases, or mixtures thereof.

In an embodiment the propellant is AP 70 which is a mixture of propane,isobutene and butane.

The propellant makes up about 5-25 wt % of the foamable composition(i.e., the ratio of the propellant to components that make up thefoamable vehicle range from about 5:100 to about 25:100). In somecircumstances the propellant may be up to about 35% or as low as about3% (i.e., the ratio of the propellant to components that make up thefoamable vehicle is from about 3:100 to about 35:100). The propellantsare used to generate and administer the foamable composition as a foam.The total composition including propellant, foamable compositions andoptional ingredients is referred to as the foamable composition.

Alcohol and organic solvents render foams inflammable. It has beensurprisingly discovered that fluorohydrocarbon propellants, other thanchloro-fluoro carbons (CMOs), which are non-ozone-depleting propellants,are particularly useful in the production of a non-flammable foamablecomposition. A test according to European Standard prEN 14851, titled“Aerosol containers—Aerosol foam flammability test” revealed thatcompositions containing an organic carrier that contains a hydrophobicorganic carrier and/or a polar solvent, which are detected asinflammable when a hydrocarbon propellant is used, become non-flammable,while the propellant is an HFC propellant.

Such propellants include, but are not limited to, hydrofluorocarbon(HFC) propellants, which contain no chlorine atoms, and as such, fallcompletely outside concerns about stratospheric ozone destruction bychlorofluorocarbons or other chlorinated hydrocarbons. Exemplarynon-flammable propellants according to this aspect of the inventioninclude propellants made by DuPont under the registered trademark Dymel,such as 1,1,1,2 tetrafluoroethane (Dymel 134), and 1,1,1,2,3,3,3heptafluoropropane (Dymel 227). HFCs possess Ozone Depletion Potentialof 0.00 and thus, they are allowed for use as propellant in aerosolproducts.

Notably, the stability of foamable emulsions including HFC as thepropellant can be improved in comparison with the same composition madewith a hydrocarbon propellant.

In one or more embodiments foamable compositions comprise a combinationof a HFC and a hydrocarbon propellant such as n-butane or mixtures ofhydrocarbon propellants such as propane, isobutane and butane. In one ormore embodiments the hydrocarbon mixture of propane, isobutane andbutane is AP70.

In one or more embodiments the foamable compositions are not selffoaming.

Microemulsions and Nanoemulsions

In some embodiments, the compositions described herein aremicroemulsions or nanoemulsions. Microemulsions and nanoemulsion aremonophasic, transparent (or slightly translucent) dispersions of oil andwater. Unlike conventional emulsions, microemulsions and nanoemulsionare thermodynamically stable, making them a favorable vehicle forpharmaceutical compositions, which have to maintain stability for longperiods of time. They and a method of manufacture are more particularlydescribed in US2006/0233721 which is incorporated herein by way ofreference. As will be appreciated by a person of skill in the art themethodology may be adapted according to the type of carrier composition.

Aging

In order to project the potential shelf life and stability of thecompositions and their ingredients particularly active or benefit agentsthe compositions can subjected to a number of tests, includingcentrifugation to look for resistance to creaming, phase separation; oneor more freeze thaw cycles, standing at room and higher temperatures asan indicator of resistance to aging.

Composition and Foam Physical Characteristics and Advantages

A pharmaceutical or cosmetic composition manufactured using the foamablecarrier is very easy to use. When applied onto the afflicted bodysurface of mammals, i.e., humans or animals, it is in a foam state,allowing free application without spillage. Upon further application ofa mechanical force, e.g., by rubbing the composition onto the bodysurface, it freely spreads on the surface and is rapidly absorbed.

The foamable composition is stable, having an acceptable shelf-life ofat least one year, or preferably, at least two years at ambienttemperature, as revealed in accelerated stability tests. The foamablecompositions according to the present invention are stable. Followingaccelerated stability studies, they demonstrate desirable texture; theyform fine bubble structures that do not break immediately upon contactwith a surface, spread easily on the treated area and absorb quickly.

The composition should also be free flowing, to allow it to flow throughthe aperture of the container, e.g., and aerosol container, and createan acceptable foam.

Foam quality can be graded as follows:

Grade E (excellent): very rich and creamy in appearance, does not showany bubble structure or shows a very fine (small) bubble structure; doesnot rapidly become dull; upon spreading on the skin, the foam retainsthe creaminess property and does not appear watery.

Grade G (good): rich and creamy in appearance, very small bubble size,“dulls” more rapidly than an excellent foam, retains creaminess uponspreading on the skin, and does not become watery.

Grade FG (fairly good): a moderate amount of creaminess noticeable,bubble structure is noticeable; upon spreading on the skin the productdulls rapidly and becomes somewhat lower in apparent viscosity.

Grade F (fair): very little creaminess noticeable, larger bubblestructure than a “fairly good” foam, upon spreading on the skin itbecomes thin in appearance and watery.

Grade P (poor): no creaminess noticeable, large bubble structure, andwhen spread on the skin it becomes very thin and watery in appearance.

Grade VP (very poor): dry foam, large very dull bubbles, difficult tospread on the skin.

Topically administrable foams are typically of quality grade E or G,when released from the aerosol container. Smaller bubbles are indicativeof more stable foam, which does not collapse spontaneously immediatelyupon discharge from the container. The finer foam structure looks andfeels smoother, thus increasing its usability and appeal.

As further aspect of the foam is breakability. The breakable foam isthermally stable, yet breaks under sheer force. Sheer-force breakabilityof the foam is clearly advantageous over thermally induced breakability.Thermally sensitive foams immediately collapse upon exposure to skintemperature and, therefore, cannot be applied on the hand and afterwardsdelivered to the afflicted area.

Another property of the foam is specific gravity, as measured uponrelease from the aerosol can. Typically, foams have specific gravity ofless than 0.12 g/mL; or less than 0.10 g/mL; or less than 0.08 g/mL,depending on their composition and on the propellant concentration.

Pharmaceutical Composition

The foamable carrier is an ideal vehicle for active pharmaceuticalingredients and active cosmetic ingredients. In the context, activepharmaceutical ingredients and active cosmetic ingredients arecollectively termed “active agent” or “active agents.” The active agentscan be used in the formulation as a suspended solid or in solution,alone or in combination with other active agents.

In one or more embodiments the active ingredient is an immune responsemodifier or antiviral agent selected from the group consisting ofimiquimod, resiquimod, and gardiquimod.

Imiquimod (4-Amino-1-isobutyl-1H-imidazo[4,5-c] quinoline) animidazoquinoline amine, is an immune response modifier used topically inthe treatment of external genital and perianal warts, superficial basalcell carcinomas, and actinic keratoses. It is applied as a 5% cream,with the frequency and period varying depending on the disease.Imiquimod is under investigation for the treatment of Bowen's diseaseand of other squamous cell carcinomas. Adverse effects after topicalapplication of imiquimod include local skin erosion, erythema,excoriation, flaking, and oedema. There have been reports of localisedhypopigmentation and hyperpigmentation. Skin reactions away from thesite of application have been reported. Imiquimod is used topically forthe treatment of external genital and perianal exophytic warts(condylomata acuminata) caused by human papillomavirus (HPV).Potentially it may have application for treating body cavity wartsurethral, intravaginal, cervical, rectal, intra-anal, or oral HPV warts.Imiquimod has been used topically for the treatment of molluscumcontagiosum and for the treatment of actinic keratoses. It may also havepotential for the topical treatment of verruca vulgaris (common warts).Alternative regimens include intralesional interferon alfa and lasersurgery. There is some evidence that warts located on moist surfacesand/or in intertriginous areas appear to respond better to topicaltreatments. On this basis in one or more embodiments, the imiquimodformulation further comprises a moisturizer and or a humectant.

Other members of the imiquimod family are resiquimod (used againstherpes simplex virus infections, including genital herpes and is apotential treatment of various other diseases, including other viralinfections and eczema and as a vaccine adjuvant) and gardiquimod (apotential antiviral).

In one or more embodiments, imiquimod is the active ingredient. It canbe used in the formulation as a suspended solid or in solution, alone orin combination with other active agents. As is known to one skilled inthe art, in some instances a specific active agent may have more thanone activity, function or effect.

Suitable active agents for use in the vehicles and formulationsdescribed herein alone or in conjunction with imiquimod include, but arenot limited to, active herbal extracts, acaricides, age spot andkeratose removing agents, allergen, analgesics, local anesthetics,antiacne agents, antiallergic agents, antiaging agents, antibacterials,antibiotics, antiburn agents, anticancer agents, antidandruff agents,antidepressants, antidermatitis agents, antiedemics, antihistamines,antihelminths, antihyperkeratolyte agents, antiinflammatory agents,antiirritants, antilipemics, antimicrobials, antimycotics,antiproliferative agents, antioxidants, anti-wrinkle agents,antipruritics, antipsoriatic agents, antirosacea agents antiseborrheicagents, antiseptic, antiswelling agents, antiviral agents, antiyeastagents, astringents, topical cardiovascular agents, chemotherapeuticagents, corticosteroids, dicarboxylic acids, disinfectants, fungicides,hair growth regulators, hormones, hydroxy acids, interferons,immunosuppressants, immunoregulating agents, insecticides, insectrepellents, keratolytic agents, lactams, metals, metal oxides,mitocides, neuropeptides, steroids, non-steroidal anti-inflammatoryagents, oxidizing agents, pediculicides, photodynamic therapy agents,retinoids, sanatives, scabicides, self tanning agents, skin whiteningagents, vasoconstrictors, vasodilators, vitamins, vitamin D derivatives,wound healing agents and wart removers as well as agents having activityagainst superficial basal cell carcinomas, actinic keratoses, Bowen'sdisease and or other squamous cell carcinomas and molluscum contagiosum.As is known to one skilled in the art, in some instances a specificactive agent may have more than one activity, function or effect.

In one or more embodiments, the formulation includes a steroidalanti-inflammatory agent. In an embodiment the wax, waxy substance,counterpart or derivative thereof is present in the composition in anamount sufficient to solubilize the steroid. Exemplary steroidalanti-inflammatory agents include, but are not limited to,corticosteroids such as bydrocortisone, hydroxyltriamcinolone,alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethsonedipropionate, clobetasol valemate, desonide, desoxymethasone,desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasonediacetate, diflucortolone valerate, fluadrenolone, flucloroloneacetonide, fludrocortisone, flumethasone pivalate, fluosinoloneacetonide, fluocinonide, flucortine butylester, fluocortolone,fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide,hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone,triamcinolone acetonide, cortisone, cortodoxone, flucetonide,fludrocortisone, difluorosone diacetate, fluradrenolone acetonide,medrysone, amcinafel, amcinafide, betamethasone and the balance of itsesters, chloroprednisone, chlorprednisone acetate, clocortelone,clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide,fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate,hydrocortisone cyclopentylpropionate, hydrocortmate, mepreddisone,paramethasone, prednisolone, prednisone, beclomethasone dipropionate,triamcinolone, and mixtures thereof

In one embodiment, the formulation includes an immunomodulator. In anembodiment the wax, waxy substance, counterpart or derivative thereof ispresent in the composition in an amount sufficient to solubilize theimmunomodulator. Immunomodulators are chemically or biologically-derivedagents that modify the immune response or the functioning of the immunesystem (as by the stimulation of antibody formation or the inhibition ofwhite blood cell activity). Immunomodulators include, among otheroptions, cyclic peptides, such as cyclosporine, tacrolimus, tresperimus,pimecrolimus, sirolimus (rapamycin), verolimus, laflunimus, laquinimodand imiquimod. Such compounds, delivered in the foam, are especiallyadvantageous in skin disorders such as psoriasis, eczema and atopicdermatitis, where the large skin areas are to be treated.

In one embodiment, the formulation includes an interferon. In anembodiment the wax, waxy substance, counterpart or derivative thereof ispresent in the composition in an amount sufficient to solubilize theinterferon.

In one embodiment, the formulation includes an podophyllin(anti-mitotic), In an embodiment the wax, waxy substance, counterpart orderivative thereof is present in the composition in an amount sufficientto solubilize the podophyllin (anti-mitotic).

In one embodiment, the formulation includes a podofilox. In anembodiment the wax, waxy substance, counterpart or derivative thereof ispresent in the composition in an amount sufficient to solubilize thepodofilox.

In one embodiment, the formulation includes a 5-fluorouracil (5-FU). Inan embodiment the wax, waxy substance, counterpart or derivative thereofis present in the composition in an amount sufficient to solubilize the5-fluorouracil (5-FU).

In an embodiment, the active agent is selected from at least one ofimiquimod, an interferon, an immunomodulator, podophyllin(anti-mitotic), podofilox, 5-fluorouracil (5-FU), and trichloroaceticacid (TCA).

In an embodiment, the active agent is selected from at least one ofFluorouracil, afovirsen, inosine pranobex, podophyllum, trichloroaceticacid, thiotep, diclofenac, 5-aminolevulinic acid and derivatives, andtretinoin.

In one or more embodiments imiquimod is used in combination withmeglumine antimoniate (for cutaneous leishmaniasis); cryotherapy [liquidnitrogen](for plantal and periungual warts/actinic keratoses); acyclovir(genital hsv-2 infection); 5-aminolevulinic acid (for genital bowenoidpapulosis); fluorouracil (anal and perianal squamous cell carcinoma;salicylic acid (anal and genital warts); a COX inhibitor sulindac (forsquamous cell carcinoma).

In one or more embodiments the composition does not contain a basicactive agent. In one or more embodiments the composition does notcontain an acidic active agent. In other embodiments the compositiondoes not contain a neutralizing active agent. In further embodiments thecomposition is not partially neutralized by the active agent. Inalternative embodiments the active agent may be basic. In still furtheralternative embodiments the active agent may be acidic. In one or moreembodiments the active agent is dissolved in the liquid wax. In one ormore preferred embodiments the liquid wax is a fatty acid. In one ormore further embodiments the solubilizing power of the liquid wax isboosted by the addition of an organic acid in combination with fattyacid. In other embodiments the solubilizing power of the liquid wax isboosted by the addition of an organic acid in combination with fattyacid and fatty alcohol. Solubilization may also be helped by thepresence of an organic hydrophobic solvent such as capric/caprylictriglycerides. In a preferred embodiment the organic acid is a hydroxyacid. Non limiting examples of alpha hydroxy acids are glycolic, lactic,citric, malic and tartaric acid. Beta hydroxy acids include salicylicacid, beta-hydroxybutyric acid, beta-hydroxy beta-methylbutyrate,carnitine, tropic acid trethocanic acid and 3-Hydroxypropionic acid. Ina preferred embodiment the hydroxy acids are liquid. In anotherembodiment the organic acid is a sugar acid including aldonic, uronicand aldaric acids. Particular examples of sugar acids are ascorbic andglucoronic acids. Included are the corresponding salts andpharmaceutically-acceptable derivatives; or any combination of any ofthe foregoing.

Because of the multiple therapeutic properties of waxes, waxysubstances, counterparts and derivatives thereof the combination of suchwaxes, waxy substances, counterparts and derivatives thereof withimiquimod or another active agents can result in a synergistictherapeutic benefit.

Encapsulation of an Active Agent

In one or more embodiments, the active agent is encapsulated inparticles, microparticles, nanoparticles, microcapsules, microspheres,nanocapsules, nanospheres, liposomes, niosomes, polymer matrix,silica-gel, graphite, nanocrystals or microsponges. Such particles canhave various functions, such as (1) protection of the active agent fromdegradation; (2) modification of the active agent release rate from thecomposition; (3) control of skin penetration profile; and (4) mitigationof adverse effects, due to the controlled release of the active agentfrom the encapsulation particles.

For example, in one embodiment, the active agent is imiquimod. Imiquimodis difficult to solubilize. For example large amounts of liquid fattyacid isostearic acid are required to solubilize the active agent.Therefore in certain embodiments imiquimod is encapsulated in particles,microparticles, nanoparticles, microcapsules, microspheres,nanocapsules, nanospheres, liposomes, niosomes, polymer matrix,silica-gel, graphite, nanocrystals or microsponges. Such particles canhave various functions, such as (1) protection of the imiquimod fromdegradation; (2) modification of the imiquimod release rate from thecomposition; (3) control of skin penetration profile; and (4) mitigationof adverse effects, due to the controlled release of the imiquimod fromthe encapsulation particles.

“Microsponges” are rigid, porous and spongelike round microscopicparticles of cross-linked polymer macroporous beads (e.g., polystyrene,copolymers thereof; methyl methacrylate/glycol dimethacrylatecrosspolymer), each defining a substantially noncollapsible porenetwork. Microsponges have a size range in between 5 to 300 μm(typically 10-25 microns) in diameter. The Microsponges can be loadedwith an active ingredient and can provide enhanced control,spreadability, safety, stability and improved aesthetic propertiesincluding controlled time release of the active ingredient to skin or toa mucosal membrane upon application of the formulation. Release istriggered, for example, by application to the skin surface such asthrough rubbing and or higher than-ambient skin temperature. The slowrelease is intended to reduce irritation by the active. Microsponge®delivery technology was developed by Advanced Polymer Systems. Examplesof drugs that have been incorporated in microsponges include ibuprofenketoprofen (non-steroidal anti-inflammatory agent), benzyl peroxide (ananti-acne agent), retinoids, such as retinoic acid and retinol,fluconazole (an antifungal agent). They can also reduce perceivedoiliness. Microsponges, when applied to the skin, release the activeagent on a time mode and also in response to other stimuli (rubbing,temperature, pH, etc). By delivering the active gradually to the skin,microsponge-benzoyl peroxide formulations, for example, have excellentefficacy with minimal irritation. Microsponges collect on the skin ormucosal surface and slowly release the entrapped agent. The emptyspheres are washed away with cleansing.

Microsponges may be incorporated in wide ranges of foam formulations. Inone or more embodiments microsponges may be incorporated into theformulations exemplified and described herein. In an embodiment theamount of microsponges may be varied from about 1% to about 25% of theformulation. In some embodiments they are from about 3% to about 15%. Inother embodiments they are from about 5% to about 15%. In an embodimentany active agent suitable for loading in microsponges may be used. Inspecific embodiments active agents such as benzyl peroxide (BPO),tretinoin, hydroquinone, ketoprofen, retinol, fluconazole, ibuprofen,trolamine, a vitamin, imiquimod and the like may be used. As can benoted from above and herein different types of active agents may beloaded into the microsponges. Accordingly, the foam formulation selectedin which to disperse the microsponges should be adapted so that theactive agent remains substantially entrapped in the microsponges. Incertain embodiments the active agent is present both in the foamformulation and in the microsponges so that some of the active agent isavailable for immediate penetration on application of the foam and thatother amounts of active agent are provided by slow or controlled releasefrom the microsponges now sitting on the topical surface. In anembodiment where the active ingredient is insoluble in water and isentrapped in the microsponges there is provided true wax in wateremulsion, where the active ingredient is only exposed to the externalwater phase and does not access the internal wax phase. In an embodimentthe foam formulation includes a large amount of hydrophobic surfactantwhich can form a tight close surfactant layer surrounding the waxdroplets sitting in the water phase to separate but still holding thewater and wax phases together as an emulsion, thereby preventing or atleast substantially reducing any leakage of active agent into the waxphase.

Fields of Applications

The foamable carrier is suitable for treating any inflicted surface. Inone or more embodiments, foamable carrier is suitable for administrationto the skin, a body surface, a body cavity or mucosal surface, e.g., thecavity and/or the mucosa of the nose, mouth, eye, ear, respiratorysystem, vagina or rectum (severally and interchangeably termed herein“target site”).

In one embodiment, the disorder is a dermatological disorder, which canbe treated by an active agent or can prevent or ameliorate the disorder.In another embodiment the disorder is a mucosal disorder.

In another embodiment, the disorder is a dermatological disorder thatbenefits from the use of imiquimod in conjunction with another activeagent. The wax, waxy substance, counterpart or derivative thereof may beof benefit by improving the solubility of the active agent or increasingthe penetration of the active agent. The wax, waxy substance,counterpart or derivative thereof may also provide a synergistictherapeutic effect in combination with the active agent.

By selecting a suitable active agent, or a combination of two or moreactive agents, the foamable composition is useful in treating an animalor a human patient having any one of a variety of dermatologicaldisorders, including dermatological pain, dermatological inflammation,acne, acne vulgaris, inflammatory acne, non-inflammatory acne, acnefulminans, nodular papulopustular acne, acne conglobata, dermatitis,bacterial skin infections, fungal skin infections, viral skininfections, parasitic skin infections, skin neoplasia, skin neoplasms,pruritis, cellulitis, acute lymphangitis, lymphadenitis, erysipelas,cutaneous abscesses, necrotizing subcutaneous infections, scalded skinsyndrome, folliculitis, furuncles, hidradenitis suppurativa, carbuncles,paronychial infections, rashes, erythrasma, impetigo, ecthyma, yeastskin infections, warts, molluscum contagiosum, trauma or injury to theskin, post-operative or post-surgical skin conditions, scabies,pediculosis, creeping eruption, eczemas, psoriasis, pityriasis rosea,lichen planus, pityriasis rubra pilaris, edematous, erythema multiforme,erythema nodosum, granuloma annulare, epidermal necrolysis, sunburn,photosensitivity, pemphigus, bullous pemphigoid, dermatitisherpetiformis, keratosis pilaris, callouses, corns, ichthyosis, skinulcers, ischemic necrosis, miliaria, hyperhidrosis, moles, Kaposi'ssarcoma, melanoma, malignant melanoma, basal cell carcinoma, squamouscell carcinoma, poison ivy, poison oak, contact dermatitis, atopicdermatitis, rosacea, purpura, moniliasis, candidiasis, baldness,alopecia, Behcet's syndrome, cholesteatoma, Dercum disease, ectodermaldysplasia, gustatory sweating, nail patella syndrome, lupus, hives, hairloss, Hailey-Hailey disease, chemical or thermal skin burns,scleroderma, aging skin, wrinkles, sun spots, necrotizing fasciitis,necrotizing myositis, gangrene, scarring, and vitiligo.

Likewise, the foamable composition is suitable for treating a disorderof a body cavity or mucosal surface, e.g., the mucosa of the nose,mouth, eye, ear, respiratory system, vagina or rectum. Non limitingexamples of such conditions include chlamydia infection, gonorrheainfection, hepatitis B, herpes, HIV/AIDS, human papillomavirus (HPV),genital warts, bacterial vaginosis, candidiasis, chancroid, granulomaInguinale, lymphogranuloma venereum, mucopurulent cervicitis (MPC),molluscum contagiosum, nongonococcal urethritis (NGU), trichomoniasis,vulvar disorders, vulvodynia, vulvar pain, yeast infection, vulvardystrophy, vulvar intraepithelial neoplasia (VIN), contact dermatitis,pelvic inflammation, endometritis, salpingitis, oophoritis, genitalcancer, cancer of the cervix, cancer of the vulva, cancer of the vagina,vaginal dryness, dyspareunia, anal and rectal disease, analabscess/fistula, anal cancer, anal fissure, anal warts, Crohn's disease,hemorrhoids, anal itch, pruritus ani, fecal incontinence, constipation,polyps of the colon and rectum.

In an embodiment, the disorder is a dermatological disorder, which canbe treated, ameliorated or prevented by a wax, waxy substance,counterpart, or derivative thereof.

In an embodiment, the disorder is a dermatological disorder, which canbe treated, ameliorated or prevented by at least one of imiquimod, aninterferon, an immunomodulator, podophyllin (anti-mitotic), podofilox,5-fluorouracil (5-FU), and trichloroacetic acid (TCA).

In an embodiment, the disorder is a dermatological disorder, which canbe treated by a topical steroid.

In an embodiment, the disorder is a dermatological disorder, which canbe treated by an immunomodulator.

In an embodiment, the disorder is a dermatological disorder, which canbe treated by an anti-infective agent, such as an antibacterial agent,and antibiotic, an antifungal agent and an antiviral agent.

In an embodiment, the disorder is a dermatological disorder, which iscommon in children. Foam is advantageous in the topical treatment ofchildren, who are sensitive to treatment with a cream or ointment.

In an embodiment, the disorder is atopic dermatitis and the active agentis a steroid.

In an embodiment, the disorder is psoriasis and the active agent is asteroid, optionally further including a DCA or DCA ester to stabilize orsolubilize the topical steroid.

In an embodiment, the disorder is selected from psoriasis and atopicdermatitis and the active agent comprises a steroid and an additionalnon-steroidal active agent, such as a vitamin D derivative, optionallyfurther including a DCA or DCA ester to stabilize or solubilize thetopical steroid and/or non-steroidal active agent.

In an embodiment, the disorder is selected from psoriasis and atopicdermatitis and the active agent comprises an immunomodulator, optionallyfurther including a DCA or DCA ester to stabilize or solubilize theimmunomodulator.

In an embodiment, the composition is useful for the treatment of aninfection. In one or more embodiments, the composition is suitable forthe treatment of an infection, selected from the group of a bacterialinfection, a fungal infection, a yeast infection, a viral infection anda parasitic infection.

In an embodiment, the composition is useful for the treatment of wound,ulcer and burn.

The composition is also suitable for administering a hormone to the skinor to a mucosal membrane or to a body cavity, in order to deliver thehormone into the tissue of the target organ, in any disorder thatresponds to treatment with a hormone.

Other foamable compositions and components for foamable compositions aredescribed in: U.S. Publication No. 05-0232869, published on Oct. 20,2005, entitled NONSTEROIDAL IMMUNOMODULATING KIT AND COMPOSITION ANDUSES THEREOF; U.S. Publication No. 05-0205086, published on Sep. 22,2005, entitled RETINOID IMMUNOMODULATING KIT AND COMPOSITION AND USESTHEREOF; U.S. Publication No. 06-0018937, published on Jan. 26, 2006,entitled STEROID KIT AND FOAMABLE COMPOSITION AND USES THEREOF; U.S.Publication No. 05-0271596, published on Dec. 8, 2005, entitledVASOACTIVE KIT AND COMPOSITION AND USES THEREOF; U.S. Publication No.06-0269485, published on Nov. 30, 2006, entitled ANTIBIOTIC KIT ANDCOMPOSITION AND USES THEREOF; U.S. Publication No. 07-0020304, publishedon Jan. 25, 2007, entitled NON-FLAMMABLE INSECTICIDE COMPOSITION ANDUSES THEREOF; U.S. Publication No. 06-0193789, published on Aug. 31,2006, entitled FILM FORMING FOAMABLE COMPOSITION; U.S. patentapplication Ser. No. 11/732,547, filed on Apr. 4, 2007, entitledANTI-INFECTION AUGMENTATION OF FOAMABLE COMPOSITIONS AND KIT AND USESTHEREOF; U.S. Provisional Patent Application No. 60/789,186, filed onApr. 4, 2006, KERATOLYTIC ANTIFUNGAL FOAM; U.S. Provisional PatentApplication No. 0/815948, filed on Jun. 23, 2006, entitled FOAMABLECOMPOSITIONS COMPRISING A CALCIUM CHANNEL BLOCKER, A CHOLINERGIC AGENTAND A NITRIC OXIDE DONOR; U.S. Provisional Patent Application No.60/818,634, filed on Jul. 5, 2006, entitled DICARBOXYLIC ACID FOAMABLEVEHICLE AND PHARMACEUTICAL COMPOSITIONS THEREOF; U.S. Provisional PatentApplication No. 60/843,140, filed on Sep. 8, 2006, entitled FOAMABLEVEHICLE AND VITAMIN PHARMACEUTICAL COMPOSITIONS THEREOF, all of whichare incorporated herein by reference in their entirety. Moreparticularly any of the active ingredients; the solvents; thesurfactants; foam adjuvants; penetration enhancers; humectants;moisturizers; and other excipients as well as the propellants listedtherein can be applied herein and are incorporated by reference.

The following examples further exemplify the benefits provided byfoamable pharmaceutical carriers described in the present application,as well as the benefits of pharmaceutical compositions thereof, methodsfor preparing the same, and therapeutic uses of the compositions. Theexamples are for the purposes of illustration only and are not intendedto be limiting. Many variations may be carried out by one of ordinaryskill in the art and are contemplated within the full scope.

Methodology

A general procedure for preparing foamable compositions is set out in WO2004/037225, which is incorporated herein by reference.

Emulsion Foam

-   -   1. Mix oily phase ingredients and heat to 75° C. to melt all        ingredients and obtain homogeneous mixture.    -   2. Mix polymers, if any, in water with heating or cooling as        appropriate for specific polymer. Whilst the polymers may be        added instead into the oily phase it was found to be        advantageous to prepare them in the water phase.    -   3. Add all other water soluble ingredients to water-polymer        solution and heat to 75° C.    -   4. Add slowly internal phase to external phase at 75° C. under        vigorous mixing and homogenize to obtain fine emulsion.        Alternatively the external phase is added slowly to the internal        phase.    -   5. Cool to below 40° C. and add sensitive ingredients with mild        mixing.    -   6. Cool to room temperature.

The above methodology may be used for the wax emulsion formulations.Reasonable changes or variations to the methodology may be introduced aswill be appreciated by someone of the art to fit a specific formulation.Specific non limiting examples appear in the Examples section below.

The methodology of loading microsponges with active agent and amountsthat can be loaded are described in WO 01/85102, which is incorporatedherein by way of reference.

Canisters, Filling and Crimping

The canisters are then filled with the formula prior to addition ofpropellant, sealed and crimped with a valve and pressurized with thepropellant. A nonlimiting exemplary procedure includes the followingsteps:

-   -   1. Each aerosol canister 35×70 mm is filled with 30±5% g of the        composition;    -   2. Each canister is closed with an aerosol valve, using a vacuum        crimping machine;    -   3. Propellant (e.g., mix of propane, butane and isobutane) is        added to each of the canisters. Canisters are then warmed for        about 30 sec in a warm bath at about 50° C. and well shaken        immediately thereafter.

Closure Integrity Test.

Each pressurized canister can be subjected to bubble and crimpingintegrity testing by immersing the canister in a 60° C. water bath for 2minutes. Canisters are observed for leakage as determined by thegeneration of bubbles. Canisters releasing bubbles are rejected.

Production Under Vacuum

Optionally, the foamable formulation may be produced under nitrogen andunder vacuum. Whilst the whole process can be carried out under anoxygen free environment, it can be sufficient to apply a vacuum afterheating and mixing all the ingredients to obtain an emulsion orhomogenous liquid. Preferably the production chamber is equipped toapply a vacuum but if not the formulation can be for example placed in adessicator to remove oxygen prior to filing and crimping.

Tests

By way of non limiting example the objectives of hardness, collapse timeand FTC stability tests are briefly set out below as would beappreciated by a person of the art.

Hardness

LFRA100 instrument is used to characterize hardness. A probe is insertedinto the test material. The resistance of the material to compression ismeasured by a calibrated load cell and reported in units of grams on thetexture analyzer instrument display. Preferably at least three repeattests are made. The textural characteristics of a dispensed foam caneffect the degree of dermal penetration, efficacy, spreadability andacceptability to the user. The results can also be looked at as anindicator of softness. Note: the foam sample is dispensed into analuminum sample holder and filled to the top of the holder.

Collapse Time

Collapse time (CT) is examined by dispensing a given quantity of foamand photographing sequentially its appearance with time duringincubation at 36° C. It is useful for evaluating foam products, whichmaintain structural stability at skin temperature for at least 1 min.Foams which are structurally stable on the skin for at least one minuteare termed “short term stable” compositions or foams.

Viscosity

Viscosity is measured with Brookfield LVDV-II+PRO with spindle SC4-25 atambient temperature and 10, 5 and 1 RPM. Viscosity is usually measuredat 10 RPM. However, at about the apparent upper limit for the spindle of˜50,000CP, the viscosity at 1 RPM may be measured, although the figuresare of a higher magnitude.

FTC (Freeze Thaw Cycles)

To check the foam appearance under extreme conditions of repeated cyclesof cooling, heating, (first cycle) cooling, heating (second cycle) etc.,commencing with −10° C. (24 hours) followed by +40° C. (24 hours)measuring the appearance and again repeating the cycle for up to threetimes.

Microscopic Examination

The procedure used for evaluating the compositions by microscopeexamination is as follows:

-   -   1) A homogenous formulation or foam produced from a homogenous        formulation is taken and a representative sample drop of foam or        pre foamed formulation as appropriate is taken and placed on a        glass slide using a capillary tube.    -   2) The drop is carefully covered with a deck glass cover slide    -   3) The sample is placed under a light microscope (Nikon eclipse        50i) for observation, using a polarizer at a magnification of        ×200. Multiple points over the area of the sample are checked.    -   4) The presence or absence of crystals is noted.    -   5) If no crystals are observed visually in the sample the        formulation is considered to be substantially free of crystals.        However, this term does not exclude the possibility of crystals        being observed at a higher magnification or occasionally in        other samples

Sensation

Healthy volunteers selected at random were give a sample of foamformulation and applied it to the skin on their hand or forearm and wereasked for their observations.

Bubble Size

Foams are made of gas bubbles entrapped in liquid. The bubble size anddistribution reflects in the visual texture and smoothness of the foam.Foam bubble size is determined by dispensing a foam sample on a glassslide, taking a picture of the foam surface with a digital cameraequipped with a macro lens. The diameter of about 30 bubbles is measuredmanually relatively to calibration standard template. Statisticalparameters such as mean bubble diameter, standard deviation andquartiles are then determined. Measuring diameter may also be undertakenwith image analysis software. The camera used was a Nikon D40× Camera(resolution 10 MP) equipped with Sigma Macro Lens (ref: APO MACRO 150 mmF2.8 EX DG HSM). Pictures obtained are cropped to keep a squared regionof 400 pixels×400 pixels. The light microscope enables observing andmeasuring particles from about a few millimeters down to about onemicron. Light microscope is limited by the visible light wavelength andtherefore is useful to measuring size of particles above 800 nanometersand practically from 1 micron (1,000 nanometers).

Shakability

“Shakability” represents the degree to which the user is able tofeel/hear the presence of the liquid contents when the filledpressurized canister is shaken. Shaking is with normal mild forcewithout vigorous shaking or excessive force. When the user cannot sensethe motion of the contents during shaking the product may be consideredto be non shakable. This property may be of particular importance incases where shaking is required for affecting proper dispersion of thecontents.

Shakability Scoring:

Good shakability (conforms to required quality specification) 2 Moderateshakability (conforms to required quality specification) 1 Not or hardlyshakable but may still be flowable and allow foam 0 formation of qualityIs substantially not able to pass through valve Block

Aging or Creaming by Centrifugation

Aging or creaming was evaluated by centrifugation, as described below:

1. Principle of test

-   -   The centrifugation used in this procedure serves as a stress        condition simulating the aging of the liquid dispersion under        investigation. Under these conditions, the centrifugal force        applied facilitates the coalescence of dispersed globules or        sedimentation of dispersed solids, resulting in loss of the        desired properties of the formulated dispersion. The presence of        some creaming at the enormous centrifugal forces imposed on the        formulations does not derogate from the fact that the        compositions have not phase separated and can still be        understood as being resistant to creaming and provides a good        indication of the long term stability of the formulations. To        the extent that good quality stable formulations are achieved,        which are resistant to creaming or such that no creaming is        observed, the formulations are considered as exceptionally        stable. The procedure is as follows: 1.1. Following preparation        of the experimental formulation/s, allow to stand at room        temperature for 24 h.    -   1.2. Handle pentane in the chemical hood. Add to each        experimental formulation in a 20-mL glass vial a quantity of        pentane equivalent to the specified quantity of propellant for        that formulation, mix and allow formulation to stand for at        least 1 h and not more than 24 h.    -   1.3. Transfer each mixture to 1.5 mL microtubes. Tap each        microtube on the table surface to remove entrapped air bubbles.    -   1.4. Place visually balanced microtubes in the centrifuge rotor        and operate the centrifuge at about 300 rpm for 10 min. about        1,000 rpm for 10 min. or at about 3,000 rpm for 10 min or at        about 10,000 rpm for 10 min. The centrifuge can be a BHG HEMLE Z        231 M.    -   1.5. Centrifugation can also be executed at a higher rpm for a        shorter period or a lower rpm for a longer period bearing in        mind the G force experienced by the formulations is many fold        greater than the one G to which a formulation would be exposed        to during its shelf life.

Intra-Canister Uniformity

Representative product containers are collected, sample test solutionsare prepared and the content of the analyte is determined according tostandard methods in the art. Variability of content is characterized aspercent difference or relative standard deviation, as appropriate,according to the number of samples evaluated.

The results ascertain variability or uniformity within a given containerin content of analytes (primarily active pharmaceutical ingredients, butalso preservatives) taken from different parts of a pressurized canisterdrug products

Two full canisters were shaken according to product instructions. About1-3 g of Foam was dispensed from each canister and discarded. Foamsufficient for two replicate sample solution preparations was thendispensed into a glass beaker. This represents the initial sample. Amiddle portion is then dispensed from each canister being about half thecanister contents. This middle dispensed portion may be discarded orcollected for testing purposes, as necessary. Foam sufficient for tworeplicate sample solution preparations was then dispensed into a glassbeaker. This represents the final sample. A small amount of formulationremains in the canister. The foam samples were stirred to remove gas/airbubbles. From both the initial and final foam portions from eachcanister 4 separate sample solutions are prepared and analyzed, 2 fromthe initial portion and 2 from the final portion. The percent differenceis calculated as follows:

$\frac{\begin{matrix}{{{Difference}\mspace{14mu} {between}\mspace{14mu} {content}\mspace{14mu} {determined}\mspace{14mu} {in}}\mspace{11mu}} \\{{{initial}\;\&}\mspace{11mu} {final}\mspace{14mu} {portions}}\end{matrix}}{\; {{{{Mean}\mspace{14mu} {of}\mspace{14mu} {content}\mspace{14mu} {of}\mspace{14mu} {initial}}\;\&}\mspace{11mu} {final}\mspace{14mu} {portions}}} \times 100$

and the intra canister uniformity evaluated from the results.

Stock Compositions

Non-limiting examples of how stock solutions are made up with andwithout API. Other stock solutions may be made using the samemethodology by simply varying adding or omitting ingredients as would beappreciated by one of the ordinary skills in the art.

EXAMPLES

The invention is described with reference to the following examples.This invention is not limited to these examples and experiments. Manyvariations will suggest themselves and are within the full intendedscope of the appended claims.

Section A—Aqueous Liquid Wax Formulations A1—Example 1—VehicleComposition Containing Isostearic Acid

The following foamable vehicles were prepared and the quality of theresultant foam was ascertained.

Ingredients 036 007 010 032 040 Isostearic acid 20 30 50 60 60 PemulenTR-2 0.62 0.4 0.4 0.3 — Polysorbate 80 3 3 3 3 3 Purified water 76.3866.6 46.6 36.7 37 Total: 100 100 100 100 100 Propellant 8 8 8 8 8 AP70Results PFF (pre foam formulation) Centrifugation 30% cr. 80% cr 90% crstable 60% cr. 3K 10% sep. Centrifugation 50% cr. 10K Microscopic No NoNo No Yes Observation Crystals Crystals Crystals Crystals Crystals FoamAppearance E E E − G E Color White White White White white Odor 1 veryfaint very faint 1 1 odor odor Shakability G = Good Good Good Good GoodDensity (g/mL) 0.045 n/a n/a 0.063 0.045 Microscopic No No No No YesObservation Crystals Crystals Crystals Crystals Crystals Collapsetime >300/FG >300/G >300/FG >300/FG 36° C. (sec) Foam pH 3.93 n/a n/a4.08 (diluted1:5)

Compositions contain 20%, 30%, 50%, 60%, isostearic acid to provide; (1)solubilizing capacity; and (2) potentially enhanced skin delivery of anactive agent and (3) some emolliency and or (4) some substantiallyorganized chaos by virtue of its non linear shape enabling bothshakability and flowability of the wax formulation and potentiallyenhanced skin penetration.

The compositions contain from about 66% to about 37% water. Therefore,they can provide a good skin feeling effect even at high concentrations.

Up to about 60% isostearic acid the compositions are believed to be waxin water emulsions. The 60% formulation was examined by water additiontest was found to be liquid wax in water emulsion despite the fact thatthe amount of liquid wax phase was approximately double that of theaqueous phase. Liquid wax in water emulsion is maintained and stabilizedby selecting a surfactant that favors liquid wax in water emulsions overwater in liquid wax emulsions. Hence, the skin feeling of thecomposition is favorable.

At about 70% isostearic acid there is significant tension to form awater in liquid wax emulsion. Using 0.4% permulen with 3% polysorbate80, which favours a liquid wax in water emulsion, did not release foamat these levels of isostearic acid. Reducing the permulen to halfresulted in a poor foam. By using PEG 30 dipolyhydroxysearate (ArlacelP-135) it is possible to form a water in liquid wax emulsion, however itproduced a poor foam with or without polymer. It is predicted though,(based on 70% oleyl alcohol foam exemplified below in Example 3), thatat about 70% isostearic acid with polysorbate 80 as surfactant and nopolymer, a foam of quality can still be produced.

Without being bound to any particular theory the physical change in theformulation may be due to isostearic acid reaching a concentration wherephase reversal from wax in water to water in wax emulsion is possible.Also at this concentration range of isostearic acid removal of thepolymeric agent, which itself can absorb water may—without being boundby any theory—perhaps reduce internal emulsion tensions resulting fromthe presence of the thickening polymeric agent and thereby unexpectedlyresulting in improved foam quality even though polymeric agents arenormally added to strengthen foam quality. Also as the concentration ofisostearic acid increased and consequently the amount of water decreasedit may be that the amount of surfactant required can be reduced as theexternal water phase is thinner.

It further appears to be the case that—without being limited by anytheory—for any given emulsion system as the liquid wax phase isincreased with a corresponding decrease in the water phase the internaltension or pressure for phase reversal will increase and the point atwhich the phase reversal can occur can be retarded by selective use ofnon traditional derivatized polymeric agents with emulsifyingproperties, such as permulen that can stabilize the formulation and helpimprove resistance to creaming they may in small amounts be able to pushback the point at which pressure for phase reversal might otherwiseoccur but subject to the caveat that whilst removal of polymer mayimprove visual foam appearance it can result in a lesser resistance tocreaming. By fine tuning of the formulations and or addition of otherstabilising substances as can be seen in Examples 2, 3, 4 and Example 8the resistance to creaming can be improved.

A foam of quality was not achieved with only permulen and isostearicacid.

These compositions can be used as a vehicle for pharmaceutical andcosmetic agents especially those soluble in liquid waxes or water. Forexample imiquimod is soluble in isostearic acid.

In order to create a foamable composition, the composition is filledinto an aerosol canister and pressurized using a liquefied or gaspropellant can be added at a concentration of about 3% to about 25%.

A1—Example 2—Vehicle Composition Containing Isostearic Acid, OleylAlcohol and Active Agent

The following foamable pharmaceutical compositions were prepared and thequality of the resultant foam was ascertained.

Ingredients 002 003 Isostearic acid 30 30 Caprilic/capric triglycerides2.5 2.5 Oleyl alcohol 7.5 7.5 Sorbitan Stearate 0.65 0.65 Imiquimod 5 5Benzyl alcohol 2 2 Xanthan gum 0.35 — Hydroxypropyl methylcellulose 0.35— Glycerin 2 2 Polysorbate 60 2.5 2.5 Methyl hydroxybenzoate 0.2 0.2Propyl hydroxybenzoate 0.02 0.02 Purified water 46.93 47.63 Total: 100100 Propellant AP70 8 8 Results PFF (pre foam formulation)Centrifugation 3K stable 55 Viscosity (cPs) 12806 18.2 MicroscopicObservation No Crystals No Crystals Foam Visual inspection HomogeneousHomogeneous (pressurized glass bottle) Appearance G G Color White WhiteOdor very faint odor very faint odor Shakability moderate Good Density(g/mL) 0.051 0.039 Microscopic Observation No Crystals No CrystalsCollapse time 36° C. (sec) >300/FG >300/FG

These compositions contain 30% isostearic acid and 7.5% oleyl alcoholand 2.5% capric caprylic triglycerides to provide (1) emolliency; (2)solubilizing capacity; and (3) potentially enhanced skin delivery of anactive agent and or (4) some organized chaos by virtue of the non linearshape of the liquid waxes enabling both shakability and flowability ofthe wax formulation and potentially enhanced skin penetration.

Formulation 02 was found to be stable to centrifugation at 3000 rpm for10 minutes indicating that it should be substantially resistant to agingand physically shelf stable.

The compositions contain about 47% water. Therefore, they provide a goodskin feeling effect.

The compositions are oil in water emulsions. Hence, the skin feeling ofthe composition is favorable.

The compositions can be used for topical therapy of a skin disordertreatable by imiquimod, which can include treating, containing,ameliorating or preventing actinic keratosis, superficial basal cellcarcinoma and external genital warts.

These compositions can be used as a vehicle for other pharmaceutical andcosmetic agents especially those soluble in liquid waxes or water.

In order to create a foamable composition, the composition is filledinto an aerosol canister and pressurized using a liquefied or gaspropellant can be added at a concentration of about 3% to about 25%.

A2—Example 3—Vehicle Composition Containing Oleyl Alcohol

The following foamable vehicles were prepared and the quality of theresultant foam was ascertained.

(a) Oleyl alcohol alone from 20% to 70%

Ingredients 037 006 009 015 031 039 044 Oleyl alcohol 20 30 50 60 60 6070 Pemulen TR-2 0.62 0.4 0.4 0.4 0.3 — — Polysorbate 80 3 3 3 3 3 3 3Purified water 76.38 66.6 46.6 36.6 36.7 37 27 Total: 100 100 100 100100 100 100 Propellant 8 8 8 8 8 8 8 AP70 Results PFF (pre foamformulation) Centrifugation 20% cr. 80% cr 90% cr — stable 60% cr. 60%cr. 3K 20% sep. Centrifugation — 50% cr. 10K Microscopic No No No — NoNo No Observation Crystals Crystals Crystals Crystals Crystals CrystalsFoam — Appearance E = E E FG = G = G G+ excellent fairly Good good ColorWhite White White — White white white Odor 1 very faint very faint — 1 11 odor odor Shakability Good Good Good — Good Good Good Density (g/mL)0.045 n/a n/a — 0.062 0.041 0.059 Microscopic No No No — No No NoObservation Crystals Crystals Crystals Crystals Crystals CrystalsCollapse time >300/FG >300/FG >300/FG — 36° C. (sec) Foam pH 3.89 4.16(diluted1:5)

The compositions contain 20%, 30%, 50%, 60%, and 70% oleyl alcohol toprovide: (1) solubilizing capacity; and (2) potentially enhanced skindelivery of an active agent and (3) some emolliency and/or (4) somesubstantially organized chaos by virtue of its non linear shape enablingboth shakability and flowability of the wax formulation and potentiallyenhanced skin penetration.

The compositions contain from about 66% to about 27% water. Therefore,they can provide a good skin feeling effect even at high concentrations.

Up to about 70% oleyl alcohol the compositions are believed to be wax inwater emulsions, The 60% and 70% formulations were examined by wateraddition test and were found to be liquid wax in water emulsions despitethe fact that the amount of liquid wax phase was approximately more thandouble that of the aqueous phase. Liquid wax in water emulsion ismaintained and stabilized by selecting a surfactant that favors liquidwax in water emulsions over water in liquid wax emulsions. Preferably,the surfactant is or comprises a non ionic surfactant. More preferablythe non ionic surfactant has a HLB (or average weighted HLB if more thanone) reasonably close to the required HLB (or average weighted requiredHLB if more than one) of the liquid wax. Other factors in the selectionof the surfactants are those in which the hydrophilic end is moredominant than the hydrophobic end; those containing a fatty acid chainat its hydrophobic end which is not dissimilar to the fatty chains ofthe liquid wax; or is a polymeric surfactant; or is a combination ofsurfactants each with one or more of these properties. Hence, the skinfeeling of the composition is favorable.

Interestingly, the method of manufacture is significant in producing afoam of good quality. For example, at 60% isostearic acid, if thepolymer is dispersed in the liquid wax phase then only fairly good foamis achieved but if instead the polymer is added the water phase to forma gel and the surfactant is then added to the gel and finally the liquidwax phase is added to the composition (as described in the methodology)then a foam of good quality is produced even though the polymer isreduced.

At about 60% there may be tension to form a water in liquid wax emulsionand at about 70% oleyl alcohol there is significant tension to form awater in liquid wax emulsion. Surprisingly, by removing the polymer at60% and at 70% oleyl alcohol the foam quality is improved.

Using 0.4% permulen with 3% polysorbate 80, which favours a liquid waxin water emulsion, did not release foam at 70% of oleyl alcohol.Increasing the surfactant to 5% or reducing the permulen to halfresulted in a poor foam.

By using PEG 30 dipolyhydroxysearate instead of polysorbate 80 it ispossible to form a water in liquid wax emulsion, however it producespoor foam with polymer and without polymer. On the other hand ifpolysorbate 80 is used as surfactant, which favours a liquid wax inwater emulsion then a foam of excellent quality is achieved withoutpolymer at 60% and at 70%.

Without being bound to any particular theory the physical change in theformulation may be due to oleyl alcohol reaching a concentration wherephase reversal from liquid wax in water to water in liquid wax emulsionis possible. Also at this concentration range of oleyl alcohol removalof the polymeric agent, which itself can absorb water may—without beingbound by any theory—perhaps reduce internal emulsion tensions resultingfrom the presence of the thickening polymeric agent and therebyunexpectedly resulting in improved foam quality even though polymericagents are normally added to strengthen foam quality. Also as theconcentration of oleyl alcohol increased and consequently the amount ofwater decreased it may be that the amount of surfactant required can bereduced as the external water phase is thinner.

It further might possibly be the case that—without being limited by anytheory—for a given emulsion system as the liquid wax phase is increasedwith a corresponding decrease in the water phase the internal tension orpressure for phase reversal will increase and the point at which thephase reversal can occur can be retarded by selective use of nontraditional derivatized polymeric agents with emulsifying properties,such as permulen that can stabilize the formulation and help improveresistance to creaming, they may in small amounts be able to push backthe point at which pressure for phase reversal might otherwise occur butsubject to the caveat that whilst removal of polymer may improve visualfoam appearance it can result in a lesser resistance to creaming. Byfine tuning of the formulations and or addition of other stabilizingsubstances resistance to creaming can be improved.

These compositions can be used as a vehicle for pharmaceutical andcosmetic agents especially those soluble in liquid waxes or water. Forexample imiquimod is soluble in isostearic acid.

Formulations 06, 09, 31, 39 and 44 were found to be substantiallyresistant to creaming when subjected to centrifugation at 3000 rpm for10 minutes. With adjustment these formulations could be stable tocentrifugation as can be seen from formulation 31, indicating that theyshould be substantially resistant to aging and physically shelf stable.

Oleyl alcohol is a defoamer and is therefore harder to formulate in foamformulations than octyldodecanol or isostearyl alcohol, which are alsoliquid fatty alcohols. Thus, by way of prophetic example the aboveformulations may be made with either octyldodecanol or isostearylalcohol alone or in combination.

In order to create a foamable composition, the composition is filledinto an aerosol canister and pressurized using a liquefied or gaspropellant can be added at a concentration of about 3% to about 25%.

3(b) 12% Oleyl Alcohol (Liquid) with 8% Isostearyl Acid (Liquid) or 8%Stearic Acid (Solid)

Ingredients HLB/RHLB 012 013 Isostearic acid 13 8.00 Stearic acid 15.58.00 Oleyl alcohol 14 12.00 12.00 Ceteareth-20 15.2 0.90 Polysorbate 8015 1.30 Glyceryl stearate 3.8 1.40 1.00 PEG 100 stearate 18.8 2.40 2.40Purified water 75.30 75.30 Total 100.00 100.00 Propellant (AP-70) 8.008.00 Appearance Quality Good-Excellent Good-Excellent Color White WhiteOdor No odor No odor Shakability Good Good Microscope No Crystals NoCrystals Density 0.038 0.044 Bubble size (μm) 144.00 93.00 Bubble size(above 0.00 0.00 500 μm)

Comments: Formulations with 12% oleyl alcohol as liquid wax were able toachieve good to excellent foam in combination either a liquid fatty acidor a solid fatty acid at 8%. As oleyl alcohol can have destabilising ordefoaming properties especially as the concentration increases thenprophetically replacing oleyl alcohol with another liquid alcohol suchas octyldodecanol or isostearyl alcohol would be expected to yieldfoamable formulations which are similar or perhaps even better.Formulation 12 had good spreadabiliy, good skin feeling and quickabsorption without a waxy sensation. Formulation 13 also had goodspreadabiliy, good skin feeling and relatively quick absorption with adelicate waxy sensation.

A1—Example 4—Vehicle Compositions Containing Jojoba Oil

The following foamable vehicles were prepared and the quality of theresultant foam was ascertained.

Ingredients 038 021 025 033 Jojoba Oil 20 50 60 70 Pemulen TR-2 0.62 0.40.3 0.22 Polysorbate 80 3 3 3 3 Purified water 76.38 46.6 36.7 26.78Control: 100 100 100 100 Propellant 8 8 8 8 AP70 Results PFF (pre foamformulation) Centrifugation 20% cr. 40% cr. 10% cr. stable 3K 20% sepCentrifugation 30% cr. 10K Viscosity (cPs) 4025 6117 Microscopic NoCrystals No Crystals No Crystals No Crystals Observation Foam AppearanceG G− G− G Color Yellowish cream cream Yellowish Odor 1 1 1 1 ShakabilityGood Moderate Moderate Moderate Density (g/mL) 0.05 0.102 0.093 0.067Microscopic No Crystals No Crystals No Crystals No Crystals ObservationCollapse time >300/G >300/G 36° C. (sec) Foam pH 3.79 3.93 4.08 4.19(diluted1:5)

These compositions contain 20%, 30%, 50%, 60%, and 70% of jojoba oil(otherwise is known as liquid wax), which somewhat resembles sebum innature to provide (1) solubilizing capacity; and (2) potentiallyenhanced skin delivery of an active agent and (3) some emolliency and or(4) some organized chaos by virtue of its non linear shape enabling bothshakability and flowability of the wax formulation and potentiallyenhanced skin penetration.

The compositions contain from about 66% to about 27% water. Therefore,they can provide a good skin feeling effect even at high concentrations.

Up to about 70% jojoba the compositions are believed to be wax in wateremulsions, Liquid wax in water emulsion is maintained and stabilized byselecting a surfactant that favors liquid wax in water emulsions overwater in liquid wax emulsions. Hence, the skin feeling of thecomposition is favorable.

Although at 70% oleyl alcohol and at 70% isostearic acid there issignificant tension to form a water in liquid wax emulsion at 70% jojobaoil the composition can still form a liquid wax in water emulsiondespite that water is only about a quarter of the composition. The extrastability of the emulsion may, without being bound to any particulartheory, be ascribed to its much longer fatty chain back bone being aboutdouble of that of oleyl alcohol and of isostearic acid.

Also at this concentration range of jojoba oil removal of the polymericagent, which itself can absorb water may—without being bound by anytheory—perhaps reduce internal emulsion tensions resulting from thepresence of the thickening polymeric agent and thereby unexpectedlyresulting in improved foam quality even though polymeric agents arenormally added to strengthen foam quality. Also as the concentration ofjojoba oil increased and consequently the amount of water decreased itmay be that the amount of surfactant required can be reduced as theexternal water phase is thinner.

It further appears to be the case that—without being limited by anytheory—for any given emulsion system as the liquid wax phase isincreased with a corresponding decrease in the water phase the internaltension or pressure for phase reversal will increase and the point atwhich the phase reversal can occur can be retarded by selective use ofnon traditional derivatized polymeric agents with emulsifyingproperties, such as permulen that can stabilize the formulation and helpimprove resistance to creaming, they may in small amounts be able topush back the point at which pressure for phase reversal might otherwiseoccur but subject to the caveat that whilst removal of polymer mayimprove visual foam appearance it can result in a lesser resistance tocreaming. By fine tuning of the formulations and or addition of otherstabilising substances resistance to creaming can be improved.

A foam of quality was not achieved with only permulen and oleyl alcohol.

These compositions can be used as a vehicle for pharmaceutical andcosmetic agents especially those soluble in liquid waxes or water. Forexample, imiquimod is soluble in isostearic acid.

In order to create a foamable composition, the composition is filledinto an aerosol canister and pressurized using a liquefied or gaspropellant can be added at a concentration of about 3% to about 25%.

Example 5 Fatty Alcohol Combination Emulsion Formulations

Ingredients HLB/RHLB 002 004 Oleyl alcohol 14 19.00 19.00 Isostearylalcohol ~13 19.00 19.00 Octyldodecanol ~14 19.00 19.00 Cetearyl alcohol15.5 2.00 3.00 Ceteareth-20 15.2 2.90 Polysorbate 60 14.9 4.00Polysorbate 80 15 2.40 Glyceryl stearate 3.8 1.00 0.70 PEG 100 stearate18.8 1.00 Sorbitane stearate 4.7 PEG-30 dipolyhydroxystearate 5.5Purified water 35.00 34.00 Total 100.00 100.00 Propellant (AP-70) 8.008.00 Appearance Quality Poor Good+ Color White Odor No odor ShakabilityGood Bubble size (μm) 149.00 Bubble size (above 500 μm) 0.00 Hardness13.13

Comments: It is possible to achieve good quality foam with highconcentrations (about 60%) of fatty alcohol emulsion formulation byusing only surfactants. The foam quality was greatly improved byincreasing the solid fatty alcohol from 2% to 3% and changing thesurfactants. The formulations may comprise a single fatty alcohol (SeeExample 3) or combinations of two or three or more fatty alcohols (SeeExample 5).

Example 6: ˜57% Isostearic Acid and 5% Imiquimod Using a PolymericSurfactant Pemulen

009 (cf Ingredients 032) Isostearic acid 56.90 Pemulen TR-2 0.30Polysorbate 80 3.00 Purified water 34.80 Imiquimod 5.00 Total 100.00Propellant AP70 8.00 Results Foam quality Good Color White Odor No OdorShakability Good Microscopic No Observation Crystals

Comments: This formulation is based on the vehicle 32 of Example 1 whichproduced good quality foam. The addition of imiquimod did notdestabilize the formulation and the imiquimod was fully dissolved withno crystals being microscopically observed.

Section B—Aqueous Solid Wax Formulations B1—Example 7—VehicleComposition Containing Stearic Acid

The following foamable vehicles were prepared and the quality of theresultant foam was ascertained.

Ingredients 024 Stearic acid 30 Polysorbate 80 10 Purified water 60Control: 100 Propellant Butane 20 Results PFF (pre foam formulation)Microscopic Observation Crystals Foam Appearance G Color whiteMicroscopic Observation Crystals

Compositions contain up to about 30% stearic acid to provide (1) someemolliency; (2) body as a waxy thickener; (3) possibly some solubilizingcapacity; and (4) possibly enhanced skin delivery of an active agent.

The compositions are wax in water emulsions and contain from about 60%water. Therefore, they can provide a good skin feeling effect even athigh stearic acid concentrations.

As a foam adjuvant in foamable formulations stearic acid is used atconcentrations of up to about 5% and preferably between about 1% andabout 3%. Beyond 5% it is used as a thickening agent although usually atlevels of not more than at about 8%. Its use beyond about 9% forfoamable compositions was thought inappropriate since it would tend tosupport the formation of a solid block from which it was not possible tomake a foam especially where traditional types of polymeric agents andor solid surfactants, were used in the formulations for example, CMC atlevels of say up to or about 5% and or steareth 21 at levels of say upto or about 5%. Surprisingly it was discovered that is was possible touse much higher levels of stearic acid to produce foamable compositionsof good quality by avoiding the use of polymeric agents, by using liquidsurfactants and by use of higher levels of hydrophobic propellant. Asthe level of stearic acid approaches about 30% it tends towards notreleasing foam. However, by selective use of liquid surfactants inhigher concentrations and or higher levels of hydrophobic propellants itwas possible to achieve a shakable flowable composition, which producedgood quality foam. Thus, the upper limit of stearic acid that can beused in a foamable composition is determined by its shakability and moreimportantly its flowability.

For example, where stearic acid is 30% and only 3% Polysorbate 80 isused poor foam is obtained. However, by increasing the liquid surfactantto about 10% so it acts as both as a solvent and as a surfactant andraising the propellant to 20% then surprisingly it was possible toobtain a foam of good quality based on a wax/water/surfactantcomposition even at such high levels of solid wax in water. Howevercrystals were observed. This problem was overcome by formulating liquidwith solid wax. Thus as can be seen in Example 7 in the presence ofliquid wax no crystals were observed in 30% stearic acid formulations.

Solid waxes form a wax in water emulsion when heated in the presence ofsurfactant with agitation, however unlike liquid wax or liquid waxysubstances they cool to form solid lipid like suspensions having uniqueroundish particles that cannot be obtained from milling, whichsuspensions nevertheless appear to be like emulsions.

A foam of quality was not achieved with only permulen and 30% stearicacid. Addition of polysorbate 80, a liquid surfactant, did not appear tomake a significant difference at a usual surfactant level of 3%.

These compositions can be used as a vehicle for pharmaceutical andcosmetic agents especially those soluble in waxes or water.

In order to create a foamable composition, the composition is filledinto an aerosol canister and pressurized using a liquefied or gaspropellant can be added at a concentration of about 3% to about 35%.Preferably between 12% to 25%.

Section C—Aqueous Formulation with Liquid and Solid Wax C1—EXAMPLE8—Vehicle Composition Containing Oleyl Alcohol, Stearyl Alcohol, CetylAlcohol and Stearic Acid

The following foamable vehicles were prepared and the quality of theresultant foam was ascertained.

Ingredients 001 Stearic acid 30 Cetyl alcohol 4 Stearyl alcohol 3Caprilic/capric triglycerides 2.5 Oleyl alcohol 7.5 Sorbitan Stearate0.65 Benzyl alcohol 2 Xanthan gum 0.35 Hydroxypropyl methylcellulose0.35 Glycerin 2 Polysorbate 60 2.5 Methyl hydroxybenzoate 0.2 Propylhydroxybenzoate 0.02 Purified water 44.93 Control: 100 Propellant AP70 8Results PFF (pre foam formulation) Microscopic Observation No CrystalsFoam Visual inspection Homogeneous (pressurized glass bottle) AppearanceG Color White Odor no odor Shakability poor Density (g/mL) 0.04Microscopic Observation No Crystals Collapse time 36° C. (sec) >300/GFoam pH (diluted1:5) 4.65

Surprisingly it was possible to make aqueous foam compositions of goodquality with solid wax of up to about 37% by addition of about 7.5%liquid wax. The upper amount of solid wax that may be added is such thatthe formulation remains substantially flowable. Also by using (andincreasing the amount of) surfactant in which the solid waxdissolves—preferably a liquid surfactant—it may be possible to increasefurther the amount of solid wax in the formulation.

C1—Example 9—Vehicle Composition Containing Isostearic Acid and StearicAcid

The following foamable vehicles were prepared and the quality of theresultant foam was ascertained.

Ingredients 023 027 029 030 Isostearic acid 40 45 55 50 Stearic acid 3025 15 20 Arlacel P-135 2 2 2 2 Sodium Chloride 0.5 0.5 0.5 0.5 Purifiedwater 27.5 27.5 27.5 27.5 Control: 100 100 100 100 Propellant AP70(except in 10 butane 8 8 8 23) Results PFF (pre foam formulation)Centrifugation 3K — 90% cr. — — Centrifugation 10K — — — Viscosity (cPs)— 12407 — — Microscopic Observation — No Crystals — — Foam — — —Appearance FG/G G FG FG Color — White — — Odor — 1 — — Shakability —Good — — Microscopic Observation — No Crystals — —

By making effective use of and combining the surprising properties ofliquid waxes with the special characteristics of solid waxes it wassurprisingly found possible to make formulations of about 70% waxes,which are shakable, flowable and form foams of fairly good and of goodquality even where solid wax is present at a concentration of 30%.

Such compositions contain 40% to 55% isostearic alcohol to provide (1)solubilizing capacity; and (2) potentially enhanced skin delivery of anactive agent and (3) some emolliency and or (4) some substantiallyorganized chaos by virtue of its non linear shape enabling bothshakability and flowability of the wax formulation and potentiallyenhanced skin penetration. In one particular embodiment, the ratio ofisostearic acid to stearic acid is about 9:5.

It is believed that even higher concentrations of isostearic acid may bereached by reducing the water alone or in combination with a reductionof stearic acid. It is also expected that replacement of isostearic acidwith oleyl alcohol would produce similar results save that—as oleylalcohol produces formulations which are a little thicker than those withthe same amount of isostearic acid—possibly the oleyl alcoholformulations might not be able to accommodate as higher level of stearicacid as can isostearic acid. Formulations with lower levels ofisostearic acid are clearly possible.

The compositions in the example contain about 27% water. Therefore, theycan provide a relatively good skin feeling effect even at such high waxconcentrations.

Formulation 27 was examined by water addition test and was found to bewater in liquid wax emulsion. By use of a surfactant favoring wax inwater emulsions as seen elsewhere in the Examples it may be possible toachieve a water in liquid wax emulsion even at these highconcentrations.

These compositions can be used as a vehicle for pharmaceutical andcosmetic agents especially those soluble in liquid waxes or water. Forexample imiquimod is soluble in isostearic acid.

In order to create a foamable composition, the composition is filledinto an aerosol canister and pressurized using a liquefied or gaspropellant can be added at a concentration of about 3% to about 25%.

C1—Example 10—Vehicle Composition Containing Isostearic Acid, One orMore of Oleyl Alcohol, Cetyl Alcohol and Stearyl Alcohol, and ActiveAgent

The following foamable vehicles were prepared and the quality of theresultant foam was ascertained.

Ingredients 003 005 006 007 Isostearic acid 30 25 25 25 Cetyl alcohol 42.2 2.2 — Stearyl alcohol 3 3.1 3.1 3.1 Caprilic/capric triglycerides2.5 — — — Oleyl alcohol 7.5 — — — White soft paraffin — 3 3 3 SorbitanStearate 0.65 0.6 0.6 0.6 PEG-40 Stearate — — — 1 Imiquimod 5 5 5 5Benzyl alcohol 2 2 2 2 Xanthan gum 0.35 0.5 0.25 0.25 Hydroxypropyl 0.350.5 0.25 0.25 methylcellulose Glycerin 2 2 2 2 Polysorbate 60 2.5 3.43.4 3.4 Methyl hydroxybenzoate 0.2 0.2 0.2 0.2 Propyl hydroxybenzoate0.02 0.02 0.02 0.02 Purified water 39.93 52.48 52.98 54.18 Control: 100100 100 100 Propellant AP70 8 8 8 8 Results Foam Quality G G/block FG GShakability shakable No shakable shakable shakability but someflowability Color White White White White Odor No odor No odor No odorNo odor Density 0.068 0.071 0.059 0.049 Collapse time (sec) >300— >300 >300 Microscopic observation No crystals No crystals No crystalsNo crystals Centrifugation 3000 rpm homogeneous homogeneous homogeneoushomogeneous

These compositions contain 30% isostearic acid and about 3% stearylalcohol. Optionally they may also contain one or more of some cetylalcohol, oleyl alcohol and capric caprylic triglycerides to provide (1)emolliency; (2) solubilizing capacity; and (3) potentially enhanced skindelivery of an active agent and or (4) some organized chaos by virtue ofthe non linear shape of the liquid waxes enabling both shakability andflowability of the wax formulation and potentially enhanced skinpenetration.

The compositions contain about 40% to about 55% water. Therefore, theyprovide a good skin feeling effect.

The compositions are oil in water emulsions. Hence, the skin feeling ofthe composition is favorable.

The compositions can be used for topical therapy of a skin disordertreatable by imiquimod, which can include treating, containing,ameliorating or preventing actinic keratosis, superficial basal cellcarcinoma and external genital warts.

These compositions can be used as a vehicle for other pharmaceutical andcosmetic agents especially those soluble in liquid waxes or water.

In order to create a foamable composition, the composition is filledinto an aerosol canister and pressurized using a liquefied or gaspropellant can be added at a concentration of about 3% to about 25%.

Example 11: Isostearic Acid and Stearic Acid EmulsionFormulations—Minimum Ingredients

Ex. 7 (029) Ex. 7 (029) cf HLB/RHLB 001- 003 Isostearic acid 13 55.0055.00 Stearic acid 15.5 15.00 15.00 Ceteareth-20 15.2 2.50 Polysorbate80 15 2.60 Sorbitane oleate 4.3 0.40 Sorbitane stearate 4.7 0.50Purified water 27.00 27.00 Total 100.00 100.00 Propellant (AP-70) 8.008.00 Appearance Quality Good− Good+ Color White White Odor No odor Noodor Shakability Good Good

Comments: It is possible to achieve good quality foam with highconcentrations (70%) of fatty acids by using only surfactants. In thetwo formulations the ratio of solid to liquid fatty acids is about 3:11.

Methodology for Formulations 001-006 in Examples 5, 11, 12 and forFormulations 012 and 013 in Example 3(b):

-   -   1) Heat all ingredients (other than water) to 60-70 C to        complete dissolution.    -   2) Heat water to 60-70 C.    -   3) Add water to 1 while mixing. Mix for about 10 minutes.    -   4) Cool to RT while mixing. Add water to adjust formulation to        100% while mixing.

Methodology for Formulation 007 in Example 12:

-   -   1) Heat all ingredients (other than water, xanthan gum,        hydroxypropyl methylcellulose, benzyl alcohol and glycerin) to        60-70 C to complete dissolution.    -   2) Add Xanthan gum and Hydroxypropyl methylcellulose to water at        RT to dissolve. Heat to 60-70 C.    -   3) Add 2 to 1 while mixing. Mix for about 10 minutes.        Alternatively I can be added to 2.    -   4) Cool to RT while mixing. Add Benzyl alcohol and Glycerin. Add        water to adjust formulation to 100% while mixing.

Methodology for Formulation 008 in Example 13:

-   -   1) Heat Isostearic acid to 60-70 C. Add Imiquimod to complete        dissolution. Add Stearic acid and PEG-30 dipolyhydroxystearate        to complete dissolution.    -   2) Add Sodium Chloride to water at RT to dissolve. Heat to 60-70        C.    -   3) Add 2 to 1 while mixing. Mix for about 10 minutes.        Alternatively I can be added to 2.    -   4) Cool to RT while mixing. Add water to adjust formulation to        100% while mixing.

Methodology for Formulation 009 in Example 6:

-   -   1) Heat Isostearic acid to 60-70 C. Add Imiquimod to complete        dissolution.    -   2) Add Pemulen TR-2 to water at RT to dissolve. Heat to 60-70 C.        Add Polysorbate 80 to complete dissolution.    -   3) Add 2 to 1 while mixing. Mix for about 10 minutes.        Alternatively I can be added to 2.    -   4) Cool to RT while mixing. Add water to adjust formulation to        100% while mixing.

Methodology for Formulation 31 in Example 5 which can be Applied to theOther Formulations in Example 5:

-   -   1) Heat Oleyl alcohol to 60-70 C.    -   2) Add Pemulen TR-2 to water at RT to dissolve. Heat to 60-70 C.        Add Polysorbate 80 to complete dissolution.    -   3) Add 2 to 1 while mixing. Mix for about 10 minutes.        Alternatively I can be added to 2.    -   4) Cool to RT while mixing. Add water to adjust formulation to        100% while mixing.

Example 12: Combination of High Fatty Acid and Fatty Alcohols EmulsionFormulations

HLB/ Ex. 6 (001) Ex. 6 (001) Ex. 6 (001) cf RHLB 005 006 007Caprilic/capric 5 2.50 2.50 10.00 triglycerides Stearic acid 15.5 30.0030.00 30.00 Oleyl alcohol 14 7.50 7.50 Cetyl alcohol 15.5 4.00 4.00 4.00Stearyl alcohol 15.5 3.00 3.00 3.00 Polysorbate 60 14.9 2.70 Polysorbate80 15 3.00 4.00 Sorbitane oleate 4.3 0.60 0.10 Sorbitane stearate 4.70.50 PEG 100 stearate 18.8 1.40 Purified water 48.00 48.90 45.10 Benzylalcohol 2.00 Glycerin 2.00 Xanthan gum 0.35 Hydroxypropyl 0.35methylcellulose Total 100.00 100.00 100.00 Propellant (AP-70) 8.00 8.008.00 Appearance Quality Good Good Good Color White White White Odor Noodor No odor No odor Shakability Poor Poor Poor Microscope Not Not Nocrystals measured measured

It is possible to achieve good foam in high concentration (47%) of fattyalcohol, fatty acid and emollient emulsion formulations by using onlysurfactants. Crystals are seen with 30% stearic acid without fattyalcohol. Surprisingly, the addition of fatty alcohols to a high level offatty acid (30%) which is otherwise insoluble results in the absence ofcrystals on microscopic observation. The presence of liquid hydrophobicsolvent may contribute to this effect.

Example 13: Emulsion Formulations with Solid and Liquid Fatty Acids

Ex. 7 (027) cf HLB/RHLB 008 Isostearic acid 13 42.70 Stearic acid 15.523.70 PEG-30 5.5 2.00 dipolyhydroxystearate Purified water 26.10 SodiumChloride 0.50 Imiquimod 5.00 Total 100.00 Propellant (AP-70) 8.00Appearance Quality Good Color White Odor No odor Shakability PoorMicroscope No crystals

It is possible to achieve good foam with high concentrations (66.4%) ofsolid and liquid fatty acids combined using only one surfactant. Theratio of solid to liquid fatty acids is about 1:2. While using liquidhydrophobic solvent, no crystals of Imiquimod were observed.

Section D—Pharmaceutical and Cosmetic Formulations D1—Example14—Exemplary Prophetic Foams Containing Active PharmaceuticalIngredients (API)

Exemplary concentrations of active ingredients in foamable compositionsare set out in Table 2 and in the following additional propheticexamples. Each active ingredient is added into, for example, any of thecarriers listed in any of the above Examples in a therapeuticallyeffective concentration and amount. The methodology of addition is wellknown to those of the art. The composition is adjusted in each case sothat it is made up to 100% w/w by addition or reduction of water or awax or waxy substance, counterpart or derivative or other solvent as isappropriate to the active agents concerned.

A—Exemplary Concentration Ranges of Some APIs which are Addable to Foams

TABLE 2 Class Concentration Exemplary Use Hydrocortisone acetate 1%Steroid responsive inflammation and psoriasis Betamethasone valerate0.12%   or atopic dermatitis Clobetasol proprionate 0.05%   Acyclovir 5%Viral infection, herpes Ciclopirox 1% Fungal infection, seborrhea,dandruff, Clindamycin   1-2% Bacterial infection, acne, rosacea, Azelaicacid 15%  Acne, rosacea, pigmentation disorder and various dermatosesMetronidazol 0.25%-2%    Rosacea, bacterial infections and parasiteinfestations Diclofenac 1% Osteoarthritus, joint pain Tacrolimus 0.2%  Atopic dermatitis, eczema and inflammation Caffeine 5% anti-celluliteClotrimazole 1% Fungal infection Lidocaine base 2% Local anaestheticTerbinafine HCL 1% Fungal infection Gentamycin 0.1%   Bacterial skininfections, burns or ulcers Dexpanthenol 5% Wounds, ulcers, minor skininfections Urea    5-10% Emollient and keratolytic Atopic dermatitis,eczema, ichthyosis and hyperkeratotic skin disorders Ammonium lactate 12%-17.5% Dry scaly conditions of the skin including ichthyosisPovidone-iodine 10%  Antimicrobial - antiseptic Benzoyl peroxide 1%-10%Acne Alpha-hydroxy acids 1%-20% Aging, wrinkles Salicylic acid 1%-10%Acne Hydroquinone 1%-10% Pigmentation disorders Calcipotriol 0.005Psoriasis Ilmiquimod 1%-5%  Skin cancers, genital warts

B—Prophetic Steroid Compositions

The following steroids can be included in carriers, compositions andfoams: betamethasone valerate 0.12%, clobetasol propionate 0.05%,betamethasone dipropionate 0.05%, fluocinolone acetonide 0.025%,hydrocortisone acetate 0.5% and hydrocortisone butyrate 0.1%.

C—Prophetic Vitamin and Steroid Compositions

Additionally, one or more of the following vitamins can be included inthe carriers, compositions and foams: vitamin C (ascorbic acid) between0.1 and 5%; for example, 0.1% 1%, 2% 3%, 4%, or 5%; vitamin C (magnesiumascorbyl phosphate) 3%, retinol 1%, retinoic acid 0.1%, niacinamide 2%and tocopherol 1% and Vitamin K. between 0.1 and 2%, for example, 0.1%or 1% or 2%.

D—Prophetic Vitamin Compositions with or without an AdditionalTherapeutic Agent

Foamable vitamin compositions at 0.1, %1%, 2%, 3%, 4%, or 5%, by weightof composition are made up with or without an active agent and added toany of the vehicles or compositions illustrated in the above Examples.

E—Prophetic Microsponge Formulations

The following microsponges can be included in any of the carriers,compositions and foams described herein or exemplified in any of thepreceding examples.

Ingredients w/w % w/w % w/w % w/w % w/w % Microsponge 1.00 3.00% 5.00%10.00% 15.00 polymer hydrophobic 99.00 97.00 95.00 90.00 85.00 wax inwater emulsion Total 100.00 100.00 100.00 100.00 100.00 Propellant AP-8-00 8-00 8-00 8-00 8-00 70%

Procedure to prepare formulations with microsponge polymer.

1.) Prepare a hydrophobic wax in water emulsion as described herein.2.) When the formulation is at room temperature, the microsponge polymerencapsulating the active agent(s) is added and the formulation is mixedfor about 5 to about 10 minutes until a uniform dispersion is obtained.Note: Where Drug Microsponge X % w/w is provided it refers to themicrosponges including the trapped drug and any other ingredientsincorporated when loading the microsponges.

E—Different Drug Classes

All the above examples represent different drug classes and it is to beunderstood that other drugs belonging to each of the classes representedabove or described elsewhere in the specification may be included andmay be used in the compositions in a safe and effective amount.

1-46. (canceled)
 47. A foam obtained from a foamable compositioncomprising a carrier and a liquefied hydrocarbon gas propellant, whereinthe carrier comprises: a) one or more liquid wax that mimics sebum,comprising at least one fatty acid and/or at least one fatty alcohol; b)a non-ionic surface-active agent; and c) water; wherein upon release ofthe foamable composition from a pressurized container a breakable foamis formed, wherein the foam comprises a micro or nanoemulsion, andwherein the foam does not comprise a polymeric agent selected from thegroup consisting of a bioadhesive agent, a gelling agent, a film formingagent, and a phase change agent.
 48. The foam of claim 47, wherein theliquid wax comprises two or more of jojoba oil, stearic acid, isostearicacid, and oleyl alcohol.
 49. The foam of claim 47, wherein, when theliquid wax comprises at least one fatty acid, the fatty acid is presentin the foamable composition at a concentration of at least about 35% byweight and wherein, when the liquid wax comprises at least one fattyalcohol, the fatty alcohol is present in the foamable composition at aconcentration of at least about 12% by weight.
 50. The foam of claim 47,wherein the liquid wax comprises a fatty acid and a fatty alcohol, andwherein the ratio of the fatty alcohol to the fatty acid is betweenabout 10:9 and about 8:1.
 51. The foam of claim 47, wherein thenon-ionic surface-active agent is present at a concentration of about0.2% to about 8% by weight of the carrier.
 52. The foam of claim 48,wherein the concentration of jojoba oil is at least 10% by weight of thefoamable composition.
 53. The foam of claim 47, comprising a second waxselected from the group consisting of: (a) a solid wax comprising atleast one fatty acid and/or at least one fatty alcohol; (b) a liquid waxcomprising at least one fatty acid and/or at least one fatty alcohol;and (c) a mixture thereof.
 54. The foam of claim 53, wherein the solidwax is substantially dissolved in the liquid wax.
 55. The foam of claim53, wherein the at least one fatty acid and/or at least one fattyalcohol has 12-22 carbon atoms in its carbon backbone.
 56. The foam ofclaim 53, wherein the solid wax is present at a concentration of atleast 7% by weight of the foamable composition.
 57. The foam of claim53, wherein the ratio of liquid wax to solid wax is between about 10:1to about 1:10.
 58. The foam of claim 47, wherein the micro ornanoemulsion is a dispersion of an organic solvent in water, wherein theorganic solvent comprises a hydrophobic organic solvent, a polarsolvent, an emollient, and/or a mixture thereof.
 59. The foam of claim58, wherein the organic solvent is at a concentration of: (a) about 2%to about 5%; (b) about 5% to about 10%; (c) about 10% to about 20%; or(d) about 20% to about 50% by weight of the carrier.
 60. The foam ofclaim 58, wherein the micro or nanoemulsion comprises organic solvent inoil globules having a number-average size of less than 500 nm.
 61. Thefoam of claim 58, wherein the micro or nanoemulsion comprisessurface-active agents having an HLB value of between 9 and
 16. 62. Thefoam of claim 58, wherein the micro or nanoemulsion comprises about 0.1%to about 5% by weight of the carrier of a non-ionic surface-active agenthaving an HLB value of between 9 and
 16. 63. The foam of claim 62,further comprising an ionic surface-active agent.
 64. The foam of claim58, further comprising about 0.1% to about 5% by weight of the carrierof a foam adjuvant selected from the group consisting of a fatty alcoholhaving 15 or more carbons in their carbon chain; a fatty acid having 16or more carbons in their carbon chain; fatty alcohols derived frombeeswax and including a mixture of alcohols, a majority of which has atleast 20 carbon atoms in their carbon chain; a fatty alcohol having atleast one double bond; a fatty acid having at least one double bond; abranched fatty alcohol; a branched fatty acid; and a fatty acidsubstituted with a hydroxyl group and mixtures thereof.
 65. The foam ofclaim 47, wherein the liquid wax comprises a fatty acid or fatty alcoholselected from the group consisting of: (a) a branched chain fatty acidor fatty alcohol; (b) a straight chain fatty acid or fatty alcohol; (c)a saturated fatty acid or fatty alcohol; (d) an unsaturated fatty acidor fatty alcohol; and (e) mixtures thereof.
 66. The foam of claim 47,wherein the ratio of the carrier to the gas propellant is about 100:3 byweight to about 100:35 by weight.
 67. The foam of claim 47, wherein theliquid wax is about 7% to about 70% by weight of the foamablecomposition.
 68. The foam of claim 47, further comprising a potentsolvent.
 69. The foam of claim 68, wherein the potent solvent is benzylalcohol.
 70. The foam of claim 47, further comprising an additionalcomponent selected from the group consisting of a modulating agent, apolar solvent, an anti perspirant, an anti-static agent, a bufferingagent, a bulking agent, a chelating agent, a colorant, a conditioner, adeodorant, a diluent, a dye, an emollient, fragrance, a humectant, anocclusive agent, a penetration enhancer, a perfuming agent, a permeationenhancer, a pH-adjusting agent, a preservative, a skin penetrationenhancer, a sunscreen, a sun blocking agent, a sunless tanning agent, avitamin, and mixtures thereof.
 71. The foam of claim 70, wherein themodulating agent comprises an antioxidant.
 72. The foam of claim 71,wherein the antioxidant is butylated hydroxy toluene.
 73. The foam ofclaim 47, further comprising an active agent.
 74. The foam of claim 73,wherein the active agent is selected from the group consisting of activeherbal extracts, acaricides, age spot and keratose removing agents,allergen, analgesics, local anesthetics, anti-acne agents, antiallergicagents, antiaging agents, antibacterials, antibiotics, antiburn agents,anticancer agents, antidandruff agents, antidepressants, antidermatitisagents, antiedemics, antihistamines, antihelminths, antihyperkeratolyteagents, antiinflammatory agents, antiirritants, antilipemics,antimicrobials, antimycotics, antiproliferative agents, antioxidants,anti-wrinkle agents, antipruritics, antipsoriatic agents, antirosaceaagents antiseborrheic agents, antiseptic agents, antiswelling agents,antiviral agents, antiyeast agents, astringents, topical cardiovascularagents, chemotherapeutic agents, corticosteroids, dicarboxylic acids,disinfectants, fungicides, hair growth regulators, hormones, hydroxyacids, immunosuppressants, immunoregulating agents, immunomodulators,insecticides, insect repellents, keratolytic agents, lactams, metals,metal oxides, mitocides, neuropeptides, steroids, non-steroidalanti-inflammatory agents, oxidizing agents, pediculicides, photodynamictherapy agents, retinoids, sanatives, scabicides, self tanning agents,skin whitening agents, vasoconstrictors, vasodilators, vitamins, vitaminD derivatives, wound healing agents, wart removers; agents havingactivity against superficial basal cell carcinomas, actinic keratoses,Bowen's disease and or other squamous cell carcinomas and molluscumcontagiosum; and agents having activity against herpes simplex virusinfections, other viral infections, eczema and a vaccine adjuvant, andmixtures thereof.
 75. The foam of claim 73, wherein the active agent isa combination of a retinoid comprising tazarotene, present at aconcentration of between about 0.005% to about 2% by weight of thefoamable composition, and a vitamin B3 or a derivative thereof.
 76. thefoam of claim 73, wherein the active agent is an anti-acne agent presentat a concentration of about 1% to about 10% by weight of the foamablecomposition.
 77. A method of treating or ameliorating a skin, mucosal orbody cavity disorder of a subject, comprising topically administering tothe subject the foam of claim
 47. 78. The method of claim 77, whereinthe disorder is selected from the group consisting of dermatologicalinflammation, acne, acne vulgaris, inflammatory acne, non-inflammatoryacne, nodular papulopustular acne, dermatitis, bacterial skininfections, hidradenitis suppurativa, molluscum contagiosum, psoriasis,pityriasis rubra pilaris, sunburn, photosensitivity, keratosis pilaris,ichthyosis, rosacea, aging skin, wrinkles, and sun spots.
 79. A foamobtained from a foamable composition comprising a carrier and aliquefied hydrocarbon gas propellant, wherein the carrier comprises: a)one or more liquid wax that mimics sebum, comprising jojoba oil; b) anon-ionic surface-active agent; and c) water; wherein upon release ofthe foamable composition from a pressurized container a breakable foamis formed, wherein the foam comprises a micro or nanoemulsion, andwherein the foam does not comprise a polymeric agent selected from thegroup consisting of a bioadhesive agent, a gelling agent, a film formingagent, and a phase change agent.
 80. The foam of claim 79, wherein theratio of the carrier to the gas propellant is about 100:3 by weight toabout 100:35 by weight.
 81. The foam of claim 79, wherein the liquid waxis about 7% to about 70% by weight of the foamable composition.
 82. Thefoam of claim 79, further comprising at least one fatty acid and/or atleast one fatty alcohol.